Noncoding genome in eye disease

C H A P T E R

5 Noncoding genome in eye disease Tadeusz J. Kaczynskia,b, Michael H. Farkasa,b,c a

Department of Ophthalmology, Jacobs School of Medicine and Biomedical Science, State University of New York at Buffalo, Buffalo, NY, United States bResearch Service, Veterans Administration Western New York Healthcare System, Buffalo, NY, United States cDepartment of Biochemistry, Jacobs School of Medicine and Biomedical Science, State University of New York at Buffalo, Buffalo, NY, United States

Introduction to the noncoding genome Research into the establishment and progression of human eye disease has long focused on protein-coding genes, and while such attention is not unwarranted, it is becoming increasingly clear that a more complete understanding requires a broader investigative scope. With the advent of next-generation sequencing, and the accompanying explosion in our knowledge of the genomic regions contributing to human disease, we have begun to appreciate the influence of the noncoding genome—the vast majority of the genome which has no protein-coding function. Functional noncoding genes are a subset of noncoding genomic loci that are transcribed into noncoding RNAs (ncRNAs) and which enact their functions without being translated into a peptide. Classes of ncRNAs are incredibly diverse and encompass ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), among others. Of the many types of ncRNAs, here we will be addressing miRNAs and lncRNAs. miRNAs, as a group, are rather well understood, while lncRNAs and their functions are not nearly so well characterized. Though we have learned much about these elements in the past few decades, we still have much to discover about how they operate to control various cellular processes and disease states. In this chapter, we can provide only a brief overview of the current understanding of these ncRNAs and their involvement in human eye diseases, but in so doing we hope to cultivate an interest in, and appreciation for, this complex issue.

Genetics and Genomics of Eye Disease https://doi.org/10.1016/B978-0-12-816222-4.00005-8

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MicroRNAs and the eye The biogenesis and regulatory mechanisms of miRNA are well understood in animals (see Ref. [1] for an excellent review of miRNAs in the metazoan lineage). Briefly, the canonical miRNA gene is transcribed by RNA polymerase II to produce a pri-miRNA transcript possessing at least one hairpin secondary structure [1]. The pri-miRNA is then cleaved by the Dicer endonuclease, and the liberated pre-miRNA hairpin is transported to the cytoplasm. Further processing of the pre-miRNA yields a single-stranded miRNA approximately 20 bp in length which is loaded into the Argonaute (AGO) protein, forming a silencing complex. Pairing of the AGO-bound miRNA to sites within messenger RNAs (mRNAs) directs those targets for posttranscriptional repression through RNA decay or translational inhibition pathways. Gene regulation by miRNAs is critical for proper development and mature cellular functioning in animals, and as such there is a broad conservation of miRNAs and their target transcripts across eumetazoan species [2–4]. It is therefore not surprising that the perturbation of miRNA pathways in the mammalian eye disrupts a normal development, a fact highlighted by the gross anatomical and physiological defects observed in mice possessing retinal-specific knockout of Dicer, which is required for miRNA maturation [5–10]. Dissection of the roles of individual miRNAs in the eye has been a protracted endeavor due to the multitudes of miRNAs, their many possible targets, and potentially subtle influence of any given interaction [11]. Yet specific sets of miRNAs have been shown to be involved in eye field specification, developmental timing, Notch signaling, and synaptic connectivity (see Ref. [12] for a thorough review of miRNAs in retinal development). Given the pivotal nodes miRNAs occupy in the retina, the question is not whether miRNA dysregulation contributes to disease states of the human eye but to what extent this is the case.

lncRNAs and the eye Due to their loose classification, it is difficult to describe lncRNAs in absolute terms without running afoul of multiple exceptions. Indeed, lncRNAs [which encompass long intervening noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes] represent an incredibly diverse group of molecules—one that will likely be partitioned into multiple, more descriptive subcategorizations as our understanding progresses. Yet for the sake of simplicity, it is worthwhile to note the general features possessed by lncRNAs: they are RNA transcripts primarily transcribed by RNA polymerase II, they possess little or no coding potential, and they are often 50 -capped, spliced, and polyadenylated [13]. Although lncRNA functions are still poorly understood, experimental evidence has thus far revealed that they largely operate in the regulation of gene expression via: (1) transcription-dependent activation or repression of genes in cis, (2) mediation of interchromosomal interactions, (3) organization of subcellular structures, (4) formation of R-loops, (5) acting as guides or decoys for transcription factors, (6) scaffolding chromatin modifying complexes, (7) acting as miRNA sponges, (8) mRNA decay regulation, or (9) regulation of protein subcellular localization [14–17]. It is critical to note that because lncRNA research is still in its infancy, there is not a clear

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consensus regarding the veracity of some of the mechanisms through which lncRNAs are believed to function. For example, the ability of lncRNAs to operate as physiologically significant miRNA sponges has been hotly debated [18–20], and although evidence has accumulated in support of the ability of lncRNAs to sponge miRNAs, the extent to which this occurs in vivo is unclear because many studies do not perform the necessary experimentation required to definitively characterize a lncRNA [21]. Importantly, the majority of lncRNAs exhibits a poor sequence conservation between species, and while it is possible for their functions to be conserved through a maintained secondary structure, extreme caution should be taken when comparing lncRNAs among disparate species [22]. In addition, many lncRNAs display a highly tissue-specific expression, and this observation, together with the low interspecies conservation, has led to the speculation that lncRNA function may be a key contributor to species-specific features [23]. With this in mind, it is imperative to remember that what holds true for a lncRNA in one species, may not be the case for another—a particularly important consideration for studies of human disease. A variety of lncRNAs have been demonstrated to be important for the proper development and functioning of the healthy eye. Studies in the murine retina have found that Tug1 is necessary for photoreceptor outer segment development [24], Rncr2 (also known as Miat or Gomafu) and Six3os regulate retinal cell fate specification [25, 26], Vax2os1 is involved in the regulation of cell cycle progression [27], and Rncr4 contributes to the organization of the retinal architecture [28]. Few studies have examined lncRNA function in healthy human retinal cells, yet given their apparent importance in retinal pigment epithelium (RPE) cell differentiation [29, 30] and their implication in retinal diseases [31], it is evident that lncRNAs are required for proper development of the human eye.

Noncoding RNAs and eye disease Our understanding of ncRNAs grows daily, and with this ever-expanding knowledge base, has come an increased interest in discovering how these molecules affect ocular diseases. Here, we will highlight a portion of the research investigating the involvement of miRNAs and lncRNAs in some of the most prominent blinding diseases: age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, retinitis pigmentosa (RP), retinoblastoma (RB), among others. In providing this overview, we hope to convey that miRNAs and lncRNAs are important players in eye disease.

Age-related macular degeneration AMD is a disease which results in the progressive deterioration of central vision, and it is the leading cause of visual impairment in the elderly population [32]. The early and intermediate forms of AMD are usually asymptomatic, and are characterized by an excessive deposition of extracellular debris (termed drusen) under the retina and altered pigmentation. Loss of retinal cells and vision occurs in the advanced stages of AMD, which are termed as either ‘wet’ or ‘dry’ owing to either the presence or absence of abnormal neovascularization beneath the retina.

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AMD pathology has been demonstrated to be influenced by altered miRNA expression (see Ref. [33] for an excellent review of miRNAs in AMD). Multiple studies have probed the AMD miRNA profile, and although some discrepancies exist between the data sets, important commonalities emerge in their comparison. Among the miRNAs most likely to be major players in AMD are miR-9, miR-34a, miR-125b, mir-146a, and miR-155; these miRNAs have been found to be upregulated in the ocular tissues and/or vitreous of AMD patients, and they target transcripts controlling the major pathological characteristics of AMD—inflammation and neovascularization [34–36]. Another study points to a possible mode of dysregulation, identifying AMD-associated variants in three miRNA genes affecting their expression levels, as well as variants in 31 coding genes possibly affecting miRNA-mRNA interactions [37]. Various miRNAs have also been suggested as useful biomarkers for AMD as serum-miRNA levels are variably altered in patients affected with different forms of the disease [38–42]. Various pathological aspects of AMD are thought to possess underpinnings in lncRNA dysregulation. Utilizing microarray and qRT-PCR assays, one study found Vax2os1 and Vax2os2 to be upregulated in a mouse model for ocular neovascularization and in the aqueous humor of patients with AMD, supporting a possibility where these two lncRNAs are involved in the angiogenesis associated with the disease [43]. Another lncRNA, RP11-234O6.2, was demonstrated to be downregulated in AMD patient RPE/choroid, and further analysis provided evidence that decreased expression of this lncRNA may contribute to AMD via diminished cell viability [44]. Additionally, because inflammation may contribute to the RPE cell dysfunction associated with AMD, another study examined how a mixture of cytokines affected the expression of lncRNAs in human RPE-derived ARPE-19 cells. The researchers were able to identify a set of lncRNAs possessing altered expression upon cytokine exposure, and they hypothesized that increased levels of BANCR (which is involved in epithelialmesenchymal transition) may link the inflammatory response with RPE cell dysfunction of AMD [45]. Furthermore, RPE cell dedifferentiation is also thought to contribute to the pathology of AMD, and the downregulation of the lncRNA ZNF503-AS1 in the RPE/choroid of AMD patients has been implicated in this process [30].

Diabetic retinopathy DR is a major complication of diabetes mellitus that involves vascular abnormalities which result in a vision loss [46]. Clinically, DR is divided into two stages. During the early, nonproliferative stage, patients can be asymptomatic but will display retinal pathologies that include microaneurysms and hemorrhages. The later, proliferative stage is characterized by retinal neovascularization, and patients may experience a severe vision loss caused by vitreous hemorrhage or retinal detachment. The most prominent of the pathological features of the DR retina are hyperglycemia, microvascular complications, inflammation, and neurodegeneration. miRNAs have been linked to DR through their involvement in the pathways leading to microvascular complications and cell death indicative of the disease. A study profiling the miRNAs expressed in the retina of a rat model of DR uncovered the upregulation of miR146a/b, miR-155, miR-132, and miR-21 [47], which have been demonstrated to be involved

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in the processes driving vitreous hemorrhaging and neovascularization that lead to disease pathology [48, 49]. Another study using a mouse genetic model of diabetes suggested that the dysregulation of Oxr1 by miR-200b contributes to the oxidative stress and retinal degeneration seen in DR [50]. Other experiments, conducted in both human and rodent cells, have shown that miR-200b [51] and miR-15ab [52] are downregulated in the diabetic state, contributing to DR pathogenesis through increased levels of the pro-angiogenic vascular endothelial growth factor (VEGF). Additionally, increased levels of miR-195 under diabetic conditions have been demonstrated to contribute to DR pathology through a diminished expression of SIRT1—an important regulator of the cell cycle, survival, and metabolism [53]. It is also interesting to note that early-stage (nonproliferative) DR has been linked to the miRNA, let-7, as its overexpression in mouse produced a phenotype mimicking symptoms of the disease, which suggests that different miRNAs may be involved depending on how far the disease has progressed [54]. Within the last few years, an increasing number of lncRNAs have been implicated in the disease processes of DR. A microarray analysis utilizing a diabetic mouse model provided some of the first indications that DR pathology may have foundations in lncRNA dysregulation—uncovering over 300 lncRNAs with altered expression levels in the diabetic retina compared to controls and highlighting the upregulation of the lncRNA, Malat1, as a good candidate for further analysis [55]. Additional experiments, conducted using knockdown strategies, have demonstrated that MALAT1 dysregulation is involved in diabetesassociated vascular defects and that MALAT1 influences the expression of genes involved in inflammation [56, 57]. Other studies have probed the connections between lncRNAs and DR pathology in both human and mouse cells, finding that under high glucose concentrations; ANRIL (also known as CDKN2B-AS1) upregulation leads to an increased expression of the pro-angiogenic VEGF, MEG3 downregulation increases angiogenesis through the disruption of the PI3K-Akt signaling axis, RNCR3 upregulation affects KLF2 transcript concentration leading to vascular dysfunction, and BDNF-AS upregulation may be involved in RPE cell apoptosis through BDNF regulation [58–61].

Glaucoma Glaucoma is an ocular disease characterized by the degenerative damage to the optic nerve which ultimately results in blindness. While the precise inciting mechanism behind the neurodegeneration of glaucoma is not yet known, it is recognized that elevated intraocular pressure (IOP) is a major risk factor for the development of the disease [62]. Increased oxidative stress is also thought to play a critical role in glaucoma pathogenesis [63]. Due to the importance of IOP in the pathology of glaucoma, there is a great interest in examining the aqueous humor of the eye for miRNAs whose dysregulation might contribute to this aspect of the disease. Interestingly, miRNA-containing extracellular vesicles appear to be used as means of communication between disparate cells over long distances (e.g., through the aqueous humor), and they are beginning to be appreciated for their diagnostic and therapeutic value in disease [64]. Indeed, in response to oxidative stress, the trabecular meshwork cells in the anterior eye have been demonstrated to release a set of miRNAs (including miR-21 and miR-450) into the aqueous humor, and these miRNAs may act as intercellular signals in

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glaucoma, affecting apoptotic pathways in retinal cells in the posterior eye [65]. Additionally, recent studies have profiled miRNAs found in the aqueous humor of the glaucomatous eye— uncovering sets of miRNAs that may be useful as potential biomarkers and may contribute to disease by altering the structure of the extracellular matrix thus influencing IOP [66, 67]. Further investigations have also revealed genetic variations affecting the expression and activity of several miRNAs (including miR-182 and miR-4707) found in the aqueous humor of glaucoma patients [68, 69]. The connection between lncRNA genotype and disease phenotype is well documented in the case of glaucoma. Multiple genome wide association studies (GWAS) in human populations of varying ethnicities have identified an association between genotypic variants at chromosomal region 9p21.3 and a susceptibility to optic nerve degeneration in glaucoma [70–73]. These variants were found to lie within the ANRIL gene locus, and although the effects of the variants remain unclear, ANRIL itself appears to confer a neuroprotective effect, as a knockout of the corresponding locus in mouse led to an increase in retinal ganglion cell (RGC) death in response to elevated IOP [74]. Interestingly, polymorphisms in the ANRIL locus have also been reported to be associated with other disparate diseases (including cardiovascular disease and cancer), and it has thus been suggested that ANRIL operates as a signaling node incorporating cell-type information with environmental stimuli [75]. Solidifying the link between glaucoma and lncRNAs, human genetic variants affecting the expression of another lncRNA, LOXL1-AS1, have been demonstrated to be strongly associated with exfoliation syndrome, which is a disorder that confers a greatly increased risk for the development of glaucoma [76].

Retinitis pigmentosa RP refers to a set of inherited retinal dystrophies wherein patients gradually lose their vision due to the progressive loss of rod and cone photoreceptor cells [77]. Most individual cases of RP are monogenic. Yet the disease is highly heterogenic, and for the most part, mutations in any one gene make up only a small proportion of the total cases of RP. Mutations causing RP have been found in genes involved in phototransduction, vitamin A metabolism, and RNA splicing, among other biochemical pathways. RP is yet another disease whose development and progression has been tied to altered expression of miRNAs. Utilizing a set of microarray and quantitative real-time PCR experiments, researchers identified a signature of miRNAs (miR-96, -182, -183, -1, and -142) differentially expressed in mouse models that mimic the pathology of the disease [78, 79]. Subsequent profiling endeavors have expanded the list of dysregulated miRNAs in mouse models of RP, and they have also begun to tease out the possible miRNA-mRNA interactions that may underlie the disease [80]. Interestingly, a set of miRNAs, known to target RP causative genes, exhibited altered expression in oxidatively stressed human RPE cells, uncovering an interwoven relationship between miRNAs, oxidative stress, and the development of RP [81]. Regarding any involvement of lncRNAs in the pathology of RP, while little is known, indications of a connection are beginning to arise in the literature. It has been documented that an excessive exposure to bright light can accelerate RP progression, and this process may

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incorporate lncRNA signaling [82]. The lncRNA, Meg3, has been demonstrated to be both proapoptotic and upregulated in the mouse retina after prolonged light exposure, and while similar studies will be necessary in human cells, it is tempting to hypothesize that MEG3-linked apoptosis might be involved in the retinal degeneration seen in light-induced RP progression [83]. Furthermore, given that certain lncRNAs, such as NEAT1 and MALAT1, are appreciated as key players in the RNA splicing process, it is possible that lncRNA dysregulation could contribute to the disruption of the splicing machinery known to be a hallmark characteristic of RNA splicing factor-associated RP [84, 85].

Retinoblastoma RB is an intraocular malignancy that originates from the retina. It is found primarily in young children, and is fatal if left untreated. Mutations in the RB1 tumor suppressor gene have been found to account for the most cases of RB, although mutations in the MYCN oncogene are now known to initiate a small percentage of RB cases [86]. The disease is genetically recessive and can be grouped into a heritable form (wherein one mutation in one allele is inherited and the other occurs de novo) and a nonheritable form (wherein mutations in both alleles occur de novo), which make up approximately 35% and 65% of cases, respectively [87]. Differential miRNA expression is believed to affect the cellular pathways leading to the development of RB. Among the first miRNAs to be studied in relation to this cancer, let-7 has been demonstrated to be downregulated in RB tumors—a particularly notable discovery as let-7 acts as tumor suppressor by regulating expression of known oncogenes [88, 89]. Similarly, dysregulation of another tumor suppressor miRNA, miR-34a, may be involved in RB progression as it displays altered expression in RB cell lines compared to control cells [90, 91]. Beyond this, additional studies have examined and identified multitudes of miRNAs that have a diagnostic and therapeutic potential for patients with RB [92, 93] (see Ref. [94] for a more comprehensive review). Only very recently have lncRNAs been investigated in relation to their possible contribution to the development of RB. The upregulation of HOTAIR in human RB tissue has been linked to aberrant Notch signaling [95], which is known to be a hallmark feature of malignant RB tumors [96]. PANDAR and LINC00152, both of which display an increased expression in RB cells and tissues, have been implicated in the progression of RB through the deregulation of apoptotic pathways [97, 98]. Additionally, BDNF-AS downregulation in RB tissues was predictive of poor survival among RB patients, and BDNF-AS overexpression inhibited proliferation and migration of RB cells [99]. Similarly, BANCR and MEG3 also demonstrate dysregulation in RB cells, and their aberrant expressions are correlated with poor prognoses [100, 101].

Other diseases of the eye Although there are many other ocular diseases aside from those mentioned above, the depth of ncRNA research with respect to these other diseases is comparatively shallow. Even so, evidence is mounting that miRNAs and lncRNAs are important players in many diseases of the eye.

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Given the fundamental role played by miRNAs in the cell, the prevalence of miRNA dysregulation in ocular diseases is not surprising. As discussed above, neovascularization plays a role in DR and AMD, but the process is also involved in the pathology of other eye diseases, such as retinopathy of prematurity, retinal vein occlusions, and ocular histoplasmosis [102]. While some miRNAs have been implicated in disease-specific neovascular pathways, many others appear to operate more generally; for example, miR-126, miR-181a, miR-351, and other miRNAs have been demonstrated to be regulators of angiogenic growth factors and are potential therapeutic targets in multiple retinal vascular diseases [103–106]. miRNA dysregulation has also been associated with proliferation and migration of RPE cells—processes that contribute to the progression of rhegmatogenous retinal detachment to the more severe proliferative vitreoretinopathy (PVR) [107–110]. Alterations in miRNA expression and activity are also implicated as causative factors in myopia, affecting key developmental pathways necessary for the proper formation of the eye and its refractivity [111, 112]. Despite being relative newcomers to the scientific scene, lncRNAs are beginning to be appreciated as pathological contributors to some less prevalent ocular diseases. One study, using a mouse model of corneal neovascularization, found 154 lncRNAs that were differentially expressed between vascularized and normal corneas [113]. Among this list of lncRNAs, two were confirmed to also be differentially expressed in the vascularized corneas of human patients, though their precise relevance to the disease has not yet been explored. Another study utilized a microarray analysis to reveal the dysregulation of 78 lncRNAs, including MALAT1, in the epiretinal tissues of patients with PVR [114]. Further investigation into the role of MALAT1 in PVR pathogenesis, demonstrated that MALAT1 is involved in the TGFβ1-induced epithelial-mesenchymal transition that is a key feature of the disease [115]. Additionally, the lncRNA, ROR, was found to be upregulated in human ocular melanoma tumor cells, compared to normal cells, and this increased expression has been implicated in processes leading to tumor growth and metastasis [116].

Concluding remarks Though it is all too evident that miRNAs and lncRNAs are important nodes in ocular diseases, much work remains to be done. A primary consideration should be in expanding our understanding of the mechanisms by which lncRNAs enact their functions. Further experimentation will also be important in uncovering the extent to which, and the molecular pathways through which, the dysregulation of any given miRNA or lncRNA contributes to a particular disorder. Furthermore, miRNAs and lncRNAs hold great promise for the diagnosis and treatment of ocular diseases, and this potential must continue to be explored.

References [1] D.P. Bartel, Metazoan microRNAs, Cell 173 (2018) 20–51. [2] E. Berezikov, Evolution of microRNA diversity and regulation in animals, Nat. Rev. Genet. 12 (2011) 846–860. [3] R.C. Friedman, K.K. Farh, C.B. Burge, D.P. Bartel, Most mammalian mRNAs are conserved targets of microRNAs, Genome Res. 19 (2009) 92–105.

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References

63

[4] J.E. Tarver, P.C. Donoghue, K.J. Peterson, Do miRNAs have a deep evolutionary history? BioEssays 34 (2012) 857–866. [5] D. Damiani, J.J. Alexander, J.R. O’Rourke, M. McManus, A.P. Jadhav, C.L. Cepko, W.W. Hauswirth, B.D. Harfe, E. Strettoi, Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina, J. Neurosci. 28 (2008) 4878–4887. [6] N. Davis, E. Mor, R. Ashery-Padan, Roles for Dicer1 in the patterning and differentiation of the optic cup neuroepithelium, Development 138 (2011) 127–138. [7] S.A. Georgi, T.A. Reh, Dicer is required for the transition from early to late progenitor state in the developing mouse retina, J. Neurosci. 30 (2010) 4048–4061. [8] A. Iida, T. Shinoe, Y. Baba, H. Mano, S. Watanabe, Dicer plays essential roles for retinal development by regulation of survival and differentiation, Invest. Ophthalmol. Vis. Sci. 52 (2011) 3008–3017. [9] N.A. Maiorano, R. Hindges, Restricted perinatal retinal degeneration induces retina reshaping and correlated structural rearrangement of the retinotopic map, Nat. Commun. 4 (2013) 1938. [10] R. Pinter, R. Hindges, Perturbations of microRNA function in mouse dicer mutants produce retinal defects and lead to aberrant axon pathfinding at the optic chiasm, PLoS ONE 5 (2010) e10021. [11] N.A. Maiorano, R. Hindges, Non-coding RNAs in retinal development, Int. J. Mol. Sci. 13 (2012) 558–578. [12] T.A. Reh, R. Hindges, MicroRNAs in retinal development, Annu. Rev. Vis. Sci. 4 (2018) 25–44. [13] J.J. Quinn, H.Y. Chang, Unique features of long non-coding RNA biogenesis and function, Nat. Rev. Genet. 17 (2016) 47–62. [14] H.M. Krause, New and prospective roles for lncRNAs in organelle formation and function, Trends Genet. 34 (10) (2018) 736–745. [15] Y. Long, X. Wang, D.T. Youmans, T.R. Cech, How do lncRNAs regulate transcription? Sci. Adv. 3 (2017) eaao2110. [16] F.P. Marchese, I. Raimondi, M. Huarte, The multidimensional mechanisms of long noncoding RNA function, Genome Biol. 18 (2017) 206. [17] J.H. Yoon, K. Abdelmohsen, J. Kim, X. Yang, J.L. Martindale, K. Tominaga-Yamanaka, E.J. White, A.V. Orjalo, J.L. Rinn, S.G. Kreft, G.M. Wilson, M. Gorospe, Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination, Nat. Commun. 4 (2013) 2939. [18] A.D. Bosson, J.R. Zamudio, P.A. Sharp, Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition, Mol. Cell 56 (2014) 347–359. [19] R. Denzler, S.E. McGeary, A.C. Title, V. Agarwal, D.P. Bartel, M. Stoffel, Impact of microRNA levels, target-site complementarity, and cooperativity on competing endogenous RNA-regulated gene expression, Mol. Cell 64 (2016) 565–579. [20] D.W. Thomson, M.E. Dinger, Endogenous microRNA sponges: evidence and controversy, Nat. Rev. Genet. 17 (2016) 272–283. [21] C.L. Smillie, T. Sirey, C.P. Ponting, Complexities of post-transcriptional regulation and the modeling of ceRNA crosstalk, Crit. Rev. Biochem. Mol. Biol. 53 (2018) 231–245. [22] I. Ulitsky, Evolution to the rescue: using comparative genomics to understand long non-coding RNAs, Nat. Rev. Genet. 17 (2016) 601–614. [23] S.U. Schmitz, P. Grote, B.G. Herrmann, Mechanisms of long noncoding RNA function in development and disease, Cell. Mol. Life Sci. 73 (2016) 2491–2509. [24] T.L. Young, T. Matsuda, C.L. Cepko, The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina, Curr. Biol. 15 (2005) 501–512. [25] N.A. Rapicavoli, E.M. Poth, S. Blackshaw, The long noncoding RNA RNCR2 directs mouse retinal cell specification, BMC Dev. Biol. 10 (2010) 49. [26] N.A. Rapicavoli, E.M. Poth, H. Zhu, S. Blackshaw, The long noncoding RNA Six3OS acts in trans to regulate retinal development by modulating Six3 activity, Neural Dev. 6 (2011) 32. [27] N. Meola, M. Pizzo, G. Alfano, E.M. Surace, S. Banfi, The long noncoding RNA Vax2os1 controls the cell cycle progression of photoreceptor progenitors in the mouse retina, RNA 18 (2012) 111–123. [28] J. Krol, I. Krol, C.P. Alvarez, M. Fiscella, A. Hierlemann, B. Roska, W. Filipowicz, A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture, Nat. Commun. 6 (2015) 7305. [29] E.D. Au, R. Fernandez-Godino, T.J. Kaczynksi, M.E. Sousa, M.H. Farkas, Characterization of lincRNA expression in the human retinal pigment epithelium and differentiated induced pluripotent stem cells, PLoS ONE 12 (2017) e0183939.

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64

5. Noncoding genome in eye disease

[30] X. Chen, C. Jiang, B. Qin, G. Liu, J. Ji, X. Sun, M. Xu, S. Ding, M. Zhu, G. Huang, B. Yan, C. Zhao, LncRNA ZNF503-AS1 promotes RPE differentiation by downregulating ZNF503 expression, Cell Death Dis. 8 (2017) e3046. [31] F. Li, X. Wen, H. Zhang, X. Fan, Novel insights into the role of Long noncoding RNA in ocular diseases, Int. J. Mol. Sci. 17 (2016) 478. [32] M.M. DeAngelis, L.A. Owen, M.A. Morrison, D.J. Morgan, M. Li, A. Shakoor, A. Vitale, S. Iyengar, D. Stambolian, I.K. Kim, L.A. Farrer, Genetics of age-related macular degeneration (AMD), Hum. Mol. Genet. 26 (2017) R45–R50. [33] P. Berber, F. Grassmann, C. Kiel, B.H. Weber, An eye on age-related macular degeneration: the role of microRNAs in disease pathology, Mol. Diagn. Ther. 21 (2017) 31–43. [34] W.J. Lukiw, B. Surjyadipta, P. Dua, P.N. Alexandrov, Common micro RNAs (miRNAs) target complement factor H (CFH) regulation in Alzheimer’s disease (AD) and in age-related macular degeneration (AMD), Int. J. Biochem. Mol. Biol. 3 (2012) 105–116. [35] C. Menard, F.A. Rezende, K. Miloudi, A. Wilson, N. Tetreault, P. Hardy, J.P. SanGiovanni, V. De Guire, P. Sapieha, MicroRNA signatures in vitreous humour and plasma of patients with exudative AMD, Oncotarget 7 (2016) 19171–19184. [36] A.I. Pogue, W.J. Lukiw, Up-regulated pro-inflammatory MicroRNAs (miRNAs) in Alzheimer’s disease (AD) and age-related macular degeneration (AMD), Cell. Mol. Neurobiol. 38 (2018) 1021–1031. [37] M. Ghanbari, S.J. Erkeland, L. Xu, J.M. Colijn, O.H. Franco, A. Dehghan, C.C.W. Klaver, M.A. Meester-Smoor, Genetic variants in microRNAs and their binding sites within gene 3’UTRs associate with susceptibility to agerelated macular degeneration, Hum. Mutat. 38 (2017) 827–838. [38] S. Ertekin, O. Yildirim, E. Dinc, L. Ayaz, S.B. Fidanci, L. Tamer, Evaluation of circulating miRNAs in wet agerelated macular regeneration, Mol. Vis. 20 (2014) 1057–1066. [39] C. Ren, Q. Liu, Q. Wei, W. Cai, M. He, Y. Du, D. Xu, Y. Wu, J. Yu, Circulating miRNAs as potential biomarkers of age-related macular degeneration, Cell. Physiol. Biochem. 41 (2017) 1413–1423. [40] J.P. SanGiovanni, P.M. SanGiovanni, P. Sapieha, V. De Guire, miRNAs, single nucleotide polymorphisms (SNPs) and age-related macular degeneration (AMD), Clin. Chem. Lab. Med. 55 (2017) 763–775. [41] M. Szemraj, A. Bielecka-Kowalska, K. Oszajca, M. Krajewska, R. Gos, P. Jurowski, M. Kowalski, J. Szemraj, Serum microRNAs as potential biomarkers of AMD, Med. Sci. Monit. 21 (2015) 2734–2742. [42] M. Szemraj, K. Oszajca, J. Szemraj, P. Jurowski, MicroRNA expression analysis in serum of patients with congenital hemochromatosis and age-related macular degeneration (AMD), Med. Sci. Monit. 23 (2017) 4050–4060. [43] X.D. Xu, K.R. Li, X.M. Li, J. Yao, J. Qin, B. Yan, Long non-coding RNAs: new players in ocular neovascularization, Mol. Biol. Rep. 41 (2014) 4493–4505. [44] W. Zhu, Y.F. Meng, Q. Xing, J.J. Tao, J. Lu, Y. Wu, Identification of lncRNAs involved in biological regulation in early age-related macular degeneration, Int. J. Nanomedicine 12 (2017) 7589–7602. [45] R.K. Kutty, W. Samuel, T. Duncan, O. Postnikova, C. Jaworski, C.N. Nagineni, T.M. Redmond, Proinflammatory cytokine interferon-gamma increases the expression of BANCR, a long non-coding RNA, in retinal pigment epithelial cells, Cytokine 104 (2018) 147–150. [46] W. Wang, A.C.Y. Lo, Diabetic retinopathy: pathophysiology and treatments, Int. J. Mol. Sci. 19 (2018). [47] B. Kovacs, S. Lumayag, C. Cowan, S. Xu, MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats, Invest. Ophthalmol. Vis. Sci. 52 (2011) 4402–4409. [48] Q. Chen, F. Qiu, K. Zhou, H.G. Matlock, Y. Takahashi, R.V.S. Rajala, Y. Yang, E. Moran, J.X. Ma, Pathogenic role of microRNA-21 in diabetic retinopathy through downregulation of PPARalpha, Diabetes 66 (2017) 1671–1682. [49] A.D. McClelland, P. Kantharidis, MicroRNA in the development of diabetic complications, Clin. Sci. (Lond) 126 (2014) 95–110. [50] A.R. Murray, Q. Chen, Y. Takahashi, K.K. Zhou, K. Park, J.X. Ma, MicroRNA-200b downregulates oxidation resistance 1 (Oxr1) expression in the retina of type 1 diabetes model, Invest. Ophthalmol. Vis. Sci. 54 (2013) 1689–1697. [51] K. McArthur, B. Feng, Y. Wu, S. Chen, S. Chakrabarti, MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy, Diabetes 60 (2011) 1314–1323. [52] Q. Wang, S. Navitskaya, H. Chakravarthy, C. Huang, N. Kady, T.A. Lydic, Y.E. Chen, K.J. Yin, F.L. Powell, P.M. Martin, M.B. Grant, J.V. Busik, Dual anti-inflammatory and anti-angiogenic action of miR-15a in diabetic retinopathy, EBioMedicine 11 (2016) 138–150.

II. Genomics in the eye

References

65

[53] R. Mortuza, B. Feng, S. Chakrabarti, miR-195 regulates SIRT1-mediated changes in diabetic retinopathy, Diabetologia 57 (2014) 1037–1046. [54] Q. Zhou, R.J.A. Frost, C. Anderson, F. Zhao, J. Ma, B. Yu, S. Wang, Let-7 contributes to diabetic retinopathy but represses pathological ocular angiogenesis, Mol. Cell. Biol. (2017). [55] B. Yan, Z.F. Tao, X.M. Li, H. Zhang, J. Yao, Q. Jiang, Aberrant expression of long noncoding RNAs in early diabetic retinopathy, Invest. Ophthalmol. Vis. Sci. 55 (2014) 941–951. [56] S. Biswas, A.A. Thomas, S. Chen, E. Aref-Eshghi, B. Feng, J. Gonder, B. Sadikovic, S. Chakrabarti, MALAT1: an epigenetic regulator of inflammation in diabetic retinopathy, Sci. Rep. 8 (2018) 6526. [57] J.Y. Liu, J. Yao, X.M. Li, Y.C. Song, X.Q. Wang, Y.J. Li, B. Yan, Q. Jiang, Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus, Cell Death Dis. 5 (2014) e1506. [58] Y. Li, F. Xu, H. Xiao, F. Han, Long noncoding RNA BDNF-AS inversely regulated BDNF and modulated highglucose induced apoptosis in human retinal pigment epithelial cells, J. Cell. Biochem. 119 (2018) 817–823. [59] G.Z. Qiu, W. Tian, H.T. Fu, C.P. Li, B. Liu, Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction, Biochem. Biophys. Res. Commun. 471 (2016) 135–141. [60] K. Shan, C.P. Li, C. Liu, X. Liu, B. Yan, RNCR3: A regulator of diabetes mellitus-related retinal microvascular dysfunction, Biochem. Biophys. Res. Commun. 482 (2017) 777–783. [61] A.A. Thomas, B. Feng, S. Chakrabarti, ANRIL: a regulator of VEGF in diabetic retinopathy, Invest. Ophthalmol. Vis. Sci. 58 (2017) 470–480. [62] A.V. Mantravadi, N. Vadhar, Glaucoma, Prim. Care 42 (2015) 437–449. [63] C. McMonnies, Reactive oxygen species, oxidative stress, glaucoma and hyperbaric oxygen therapy, J. Optom. 11 (2018) 3–9. [64] S.N. Blandford, D.A. Galloway, C.S. Moore, The roles of extracellular vesicle microRNAs in the central nervous system, Glia 66 (11) (2018) 2267–2278. [65] A. Izzotti, C. Ceccaroli, M.G. Longobardi, R.T. Micale, A. Pulliero, S. La Maestra, S.C. Sacca, Molecular damage in Glaucoma: from anterior to posterior eye segment. The microRNA role, Microrna 4 (2015) 3–17. [66] M.D. Drewry, P. Challa, J.G. Kuchtey, I. Navarro, I. Helwa, Y. Hu, H. Mu, W.D. Stamer, R.W. Kuchtey, Y. Liu, Differentially expressed microRNAs in the aqueous humor of patients with exfoliation glaucoma or primary open-angle glaucoma, Hum. Mol. Genet. 27 (2018) 1263–1275. [67] H. Jayaram, J.I. Phillips, D.C. Lozano, T.E. Choe, W.O. Cepurna, E.C. Johnson, J.C. Morrison, D.M. Gattey, J.A. Saugstad, K.E. Keller, Comparison of microRNA expression in aqueous humor of normal and primary open-angle Glaucoma patients using PCR arrays: a pilot study, Invest. Ophthalmol. Vis. Sci. 58 (2017) 2884–2890. [68] M. Ghanbari, A.I. Iglesias, H. Springelkamp, C.M. van Duijn, M.A. Ikram, A. Dehghan, S.J. Erkeland, C.C.W. Klaver, M.A. Meester-Smoor, Consortium International Glaucoma Genetics, A genome-wide scan for microRNA-related genetic variants associated with primary open-angle Glaucoma, Invest. Ophthalmol. Vis. Sci. 58 (2017) 5368–5377. [69] Y. Liu, J.C. Bailey, I. Helwa, W.M. Dismuke, J. Cai, M. Drewry, M.H. Brilliant, D.L. Budenz, W.G. Christen, D.I. Chasman, J.H. Fingert, D. Gaasterland, T. Gaasterland, M.O. Gordon, R.P. Igo Jr., J.H. Kang, M.A. Kass, P. Kraft, R.K. Lee, P. Lichter, S.E. Moroi, A. Realini, J.E. Richards, R. Ritch, J.S. Schuman, W.K. Scott, K. Singh, A.J. Sit, Y.E. Song, D. Vollrath, R. Weinreb, F. Medeiros, G. Wollstein, D.J. Zack, K. Zhang, M.A. Pericak-Vance, P. Gonzalez, W.D. Stamer, J. Kuchtey, R.W. Kuchtey, R.R. Allingham, M.A. Hauser, L.R. Pasquale, J.L. Haines, J.L. Wiggs, A common variant in MIR182 is associated with primary open-angle Glaucoma in the NEIGHBORHOOD consortium, Invest. Ophthalmol. Vis. Sci. 57 (2016) 3974–3981. [70] K.P. Burdon, A. Crawford, R.J. Casson, A.W. Hewitt, J. Landers, P. Danoy, D.A. Mackey, P. Mitchell, P.R. Healey, J.E. Craig, Glaucoma risk alleles at CDKN2B-AS1 are associated with lower intraocular pressure, normal-tension glaucoma, and advanced glaucoma, Ophthalmology 119 (2012) 1539–1545. [71] M. Nakano, Y. Ikeda, Y. Tokuda, M. Fuwa, N. Omi, M. Ueno, K. Imai, H. Adachi, M. Kageyama, K. Mori, S. Kinoshita, K. Tashiro, Common variants in CDKN2B-AS1 associated with optic-nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese, PLoS ONE 7 (2012) e33389. [72] L.R. Pasquale, S.J. Loomis, J.H. Kang, B.L. Yaspan, W. Abdrabou, D.L. Budenz, T.C. Chen, E. Delbono, D.S. Friedman, D. Gaasterland, T. Gaasterland, C.L. Grosskreutz, R.K. Lee, P.R. Lichter, Y. Liu, C.A. McCarty, S.E. Moroi, L.M. Olson, T. Realini, D.J. Rhee, J.S. Schuman, K. Singh, D. Vollrath, G. Wollstein, D.J. Zack, R.R. Allingham, M.A. Pericak-Vance, R.N. Weinreb, K. Zhang, M.A. Hauser,

II. Genomics in the eye

66

[73]

[74] [75] [76]

[77] [78] [79] [80]

[81] [82] [83]

[84] [85] [86]

[87] [88]

[89] [90] [91]

5. Noncoding genome in eye disease

J.E. Richards, J.L. Haines, J.L. Wiggs, CDKN2B-AS1 genotype-glaucoma feature correlations in primary openangle glaucoma patients from the United States, Am. J. Ophthalmol. 155 (2013) 342–53 e5. J.L. Wiggs, B.L. Yaspan, M.A. Hauser, J.H. Kang, R.R. Allingham, L.M. Olson, W. Abdrabou, B.J. Fan, D.Y. Wang, W. Brodeur, D.L. Budenz, J. Caprioli, A. Crenshaw, K. Crooks, E. Delbono, K.F. Doheny, D.S. Friedman, D. Gaasterland, T. Gaasterland, C. Laurie, R.K. Lee, P.R. Lichter, S. Loomis, Y. Liu, F.A. Medeiros, C. McCarty, D. Mirel, S.E. Moroi, D.C. Musch, A. Realini, F.W. Rozsa, J.S. Schuman, K. Scott, K. Singh, J.D. Stein, E.H. Trager, P. Vanveldhuisen, D. Vollrath, G. Wollstein, S. Yoneyama, K. Zhang, R.N. Weinreb, J. Ernst, M. Kellis, T. Masuda, D. Zack, J.E. Richards, M. Pericak-Vance, L.R. Pasquale, J.L. Haines, Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma, PLoS Genet. 8 (2012) e1002654. S. Gao, T.C. Jakobs, Mice homozygous for a deletion in the Glaucoma susceptibility locus INK4 show increased vulnerability of retinal ganglion cells to elevated intraocular pressure, Am. J. Pathol. 186 (2016) 985–1005. A. Congrains, K. Kamide, M. Ohishi, H. Rakugi, ANRIL: molecular mechanisms and implications in human health, Int. J. Mol. Sci. 14 (2013) 1278–1292. M.A. Hauser, I.F. Aboobakar, Y. Liu, S. Miura, B.T. Whigham, P. Challa, J. Wheeler, A. Williams, C. SantiagoTurla, X. Qin, R.M. Rautenbach, A. Ziskind, M. Ramsay, S. Uebe, L. Song, A. Safi, E.N. Vithana, T. Mizoguchi, S. Nakano, T. Kubota, K. Hayashi, S. Manabe, S. Kazama, Y. Mori, K. Miyata, N. Yoshimura, A. Reis, G.E. Crawford, F. Pasutto, T.R. Carmichael, S.E. Williams, M. Ozaki, T. Aung, C.C. Khor, W.D. Stamer, A.E. Ashley-Koch, R.R. Allingham, Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus, Hum. Mol. Genet. 24 (2015) 6552–6563. D.T. Hartong, E.L. Berson, T.P. Dryja, Retinitis pigmentosa, Lancet 368 (2006) 1795–1809. C.J. Loscher, K. Hokamp, P.F. Kenna, A.C. Ivens, P. Humphries, A. Palfi, G.J. Farrar, Altered retinal microRNA expression profile in a mouse model of retinitis pigmentosa, Genome Biol. 8 (2007) R248. C.J. Loscher, K. Hokamp, J.H. Wilson, T. Li, P. Humphries, G.J. Farrar, A. Palfi, A common microRNA signature in mouse models of retinal degeneration, Exp. Eye Res. 87 (2008) 529–534. A. Anasagasti, M. Ezquerra-Inchausti, O. Barandika, M. Munoz-Culla, M.M. Caffarel, D. Otaegui, A. Lopez de Munain, J. Ruiz-Ederra, Expression profiling analysis reveals key MicroRNA-mRNA interactions in early retinal degeneration in retinitis pigmentosa, Invest. Ophthalmol. Vis. Sci. 59 (2018) 2381–2392. L. Donato, P. Bramanti, C. Scimone, C. Rinaldi, R. D’Angelo, A. Sidoti, miRNA expression profile of retinal pigment epithelial cells under oxidative stress conditions, FEBS Open Bio 8 (2018) 219–233. D.M. Paskowitz, M.M. LaVail, J.L. Duncan, Light and inherited retinal degeneration, Br. J. Ophthalmol. 90 (2006) 1060–1066. Y.X. Zhu, J. Yao, C. Liu, H.T. Hu, X.M. Li, H.M. Ge, Y.F. Zhou, K. Shan, Q. Jiang, B. Yan, Long non-coding RNA MEG3 silencing protects against light-induced retinal degeneration, Biochem. Biophys. Res. Commun. 496 (2018) 1236–1242. N. Romero-Barrios, M.F. Legascue, M. Benhamed, F. Ariel, M. Crespi, Splicing regulation by long noncoding RNAs, Nucleic Acids Res. 46 (2018) 2169–2184. M.M. Scotti, M.S. Swanson, RNA mis-splicing in disease, Nat. Rev. Genet. 17 (2016) 19–32. D.E. Rushlow, B.M. Mol, J.Y. Kennett, S. Yee, S. Pajovic, B.L. Theriault, N.L. Prigoda-Lee, C. Spencer, H. Dimaras, T.W. Corson, R. Pang, C. Massey, R. Godbout, Z. Jiang, E. Zacksenhaus, K. Paton, A.C. Moll, C. Houdayer, A. Raizis, W. Halliday, W.L. Lam, P.C. Boutros, D. Lohmann, J.C. Dorsman, B.L. Gallie, Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies, Lancet Oncol. 14 (2013) 327–334. R. Rao, S.G. Honavar, Retinoblastoma, Indian J. Pediatr. 84 (2017) 937–944. G. Mu, H. Liu, F. Zhou, X. Xu, H. Jiang, Y. Wang, Y. Qu, Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas, Hum. Pathol. 41 (2010) 493–502. B.L. Theriault, H. Dimaras, B.L. Gallie, T.W. Corson, The genomic landscape of retinoblastoma: a review, Clin. Exp. Ophthalmol. 42 (2014) 33–52. C.L. Dalgard, M. Gonzalez, J.E. deNiro, J.M. O’Brien, Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells, Invest. Ophthalmol. Vis. Sci. 50 (2009) 4542–4551. A.H. Reis, F.R. Vargas, B. Lemos, More epigenetic hits than meets the eye: microRNAs and genes associated with the tumorigenesis of retinoblastoma, Front. Genet. 3 (2012) 284.

II. Genomics in the eye

References

67

[92] B.E. Castro-Magdonel, M. Orjuela, J. Camacho, A.J. Garcia-Chequer, L. Cabrera-Munoz, S. Sadowinski-Pine, N. Duran-Figueroa, M.J. Orozco-Romero, A.C. Velazquez-Wong, A. Hernandez-Angeles, C. HernandezGalvan, C. Lara-Molina, M.V. Ponce-Castaneda, miRNome landscape analysis reveals a 30 miRNA core in retinoblastoma, BMC Cancer 17 (2017) 458. [93] Y. Yang, Q. Mei, miRNA signature identification of retinoblastoma and the correlations between differentially expressed miRNAs during retinoblastoma progression, Mol. Vis. 21 (2015) 1307–1317. [94] K. Golabchi, R. Soleimani-Jelodar, N. Aghadoost, F. Momeni, A. Moridikia, J.S. Nahand, A. Masoudifar, H. Razmjoo, H. Mirzaei, MicroRNAs in retinoblastoma: potential diagnostic and therapeutic biomarkers, J. Cell. Physiol. 233 (2018) 3016–3023. [95] C. Dong, S. Liu, Y. Lv, C. Zhang, H. Gao, L. Tan, H. Wang, Long non-coding RNA HOTAIR regulates proliferation and invasion via activating notch signalling pathway in retinoblastoma, J. Biosci. 41 (2016) 677–687. [96] W. Xiao, X. Chen, M. He, Inhibition of the jagged/notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/betacatenin signaling pathways, Mol. Med. Rep. 10 (2014) 453–458. [97] S. Li, D. Wen, S. Che, Z. Cui, Y. Sun, H. Ren, J. Hao, Knockdown of long noncoding RNA 00152 (LINC00152) inhibits human retinoblastoma progression, Onco Targets Ther. 11 (2018) 3215–3223. [98] L. Sheng, J. Wu, X. Gong, D. Dong, X. Sun, SP1-induced upregulation of lncRNA PANDAR predicts adverse phenotypes in retinoblastoma and regulates cell growth and apoptosis in vitro and in vivo, Gene 668 (2018) 140–145. [99] W. Shang, Y. Yang, J. Zhang, Q. Wu, Long noncoding RNA BDNF-AS is a potential biomarker and regulates cancer development in human retinoblastoma, Biochem. Biophys. Res. Commun. 497 (2018) 1142–1148. [100] Y. Gao, X. Lu, Decreased expression of MEG3 contributes to retinoblastoma progression and affects retinoblastoma cell growth by regulating the activity of Wnt/beta-catenin pathway, Tumour Biol. 37 (2016) 1461–1469. [101] S. Su, J. Gao, T. Wang, J. Wang, H. Li, Z. Wang, Long non-coding RNA BANCR regulates growth and metastasis and is associated with poor prognosis in retinoblastoma, Tumour Biol. 36 (2015) 7205–7211. [102] P.A. Campochiaro, Ocular neovascularization, J. Mol. Med. (Berl) 91 (2013) 311–321. [103] Y. Bai, X. Bai, Z. Wang, X. Zhang, C. Ruan, J. Miao, MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors, Exp. Mol. Pathol. 91 (2011) 471–477. [104] J. Shen, X. Yang, B. Xie, Y. Chen, M. Swaim, S.F. Hackett, P.A. Campochiaro, MicroRNAs regulate ocular neovascularization, Mol. Ther. 16 (2008) 1208–1216. [105] C. Yang, H. Tahiri, C. Cai, M. Gu, C. Gagnon, P. Hardy, MicroRNA-181a inhibits ocular neovascularization by interfering with vascular endothelial growth factor expression, Cardiovasc. Ther. 36 (2018) e12329. [106] R. Zhao, L. Qian, L. Jiang, miRNA-dependent cross-talk between VEGF and Ang-2 in hypoxia-induced microvascular dysfunction, Biochem. Biophys. Res. Commun. 452 (2014) 428–435. [107] K. Takayama, H. Kaneko, S.J. Hwang, F. Ye, A. Higuchi, T. Tsunekawa, T. Matsuura, T. Iwase, T. Asami, Y. Ito, S. Ueno, S. Yasuda, N. Nonobe, H. Terasaki, Increased ocular levels of MicroRNA-148a in cases of retinal detachment promote epithelial-mesenchymal transition, Invest. Ophthalmol. Vis. Sci. 57 (2016) 2699–2705. [108] T. Tsunekawa, H. Kaneko, K. Takayama, S.J. Hwang, A. Oishi, Y. Nagasaka, F. Ye, T. Iwase, N. Nonobe, S. Ueno, Y. Ito, S. Yasuda, T. Matsuura, H. Shimizu, A. Suzumura, K. Kataoka, H. Terasaki, Correlation between miR-148 expression in vitreous and severity of rhegmatogenous retinal detachment, Biomed. Res. Int. 2017 (2017) 3427319. [109] A. Usui-Ouchi, Y. Ouchi, M. Kiyokawa, T. Sakuma, R. Ito, N. Ebihara, Upregulation of Mir-21 levels in the vitreous humor is associated with development of proliferative vitreoretinal disease, PLoS ONE 11 (2016) e0158043. [110] L. Wang, F. Dong, P.S. Reinach, D. He, X. Zhao, X. Chen, D.N. Hu, D. Yan, MicroRNA-182 suppresses HGF/SFinduced increases in retinal pigment epithelial cell proliferation and migration through targeting c-met, PLoS ONE 11 (2016) e0167684. [111] K.C. Chen, E. Hsi, C.Y. Hu, W.W. Chou, C.L. Liang, S.H. Juo, MicroRNA-328 may influence myopia development by mediating the PAX6 gene, Invest. Ophthalmol. Vis. Sci. 53 (2012) 2732–2739. [112] A.V. Tkatchenko, X. Luo, T.V. Tkatchenko, C. Vaz, V.M. Tanavde, S. Maurer-Stroh, S. Zauscher, P. Gonzalez, T.L. Young, Large-scale microRNA expression profiling identifies putative retinal miRNA-mRNA signaling pathways underlying form-deprivation myopia in mice, PLoS ONE 11 (2016) e0162541.

II. Genomics in the eye

68

5. Noncoding genome in eye disease

[113] J. Huang, Y.J. Li, J.Y. Liu, Y.Y. Zhang, X.M. Li, L.N. Wang, J. Yao, Q. Jiang, B. Yan, Identification of corneal neovascularization-related long noncoding RNAs through microarray analysis, Cornea 34 (2015) 580–587. [114] R.M. Zhou, X.Q. Wang, J. Yao, Y. Shen, S.N. Chen, H. Yang, Q. Jiang, B. Yan, Identification and characterization of proliferative retinopathy-related long noncoding RNAs, Biochem. Biophys. Res. Commun. 465 (2015) 324–330. [115] S. Yang, H. Yao, M. Li, H. Li, F. Wang, Long non-coding RNA MALAT1 mediates transforming growth factor Beta1-induced epithelial-mesenchymal transition of retinal pigment epithelial cells, PLoS ONE 11 (2016) e0152687. [116] J. Fan, Y. Xing, X. Wen, R. Jia, H. Ni, J. He, X. Ding, H. Pan, G. Qian, S. Ge, A.R. Hoffman, H. Zhang, X. Fan, Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis, Genome Biol. 16 (2015) 139.

II. Genomics in the eye