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Genetics of aging, progeria and lamin disorders
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ScienceDirect Genetics of aging, progeria and lamin disorders Shrestha Ghosh1 and Zhongjun Zhou1,2 Premature aging disorders, like Werner syndrome, Bloom’s syndrome, and Hutchinson–Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways involved in the maintenance of genomic integrity, thus suggesting a profound impact of the nuclear lamina in nuclear organization, chromatin dynamics, regulation of gene expression and epigenetics. Addresses 1 Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 2 Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China Corresponding author: Zhou, Zhongjun ([email protected])
Current Opinion in Genetics & Development 2014, 26:41–46 This review comes from a themed issue on Molecular and genetic bases of disease Edited by Cynthia T McMurray and Jan Vijg
Physiological and premature aging: from the perspective of genetics The prominence of genetic contribution to aging was primarily advocated by two theories, somatic mutation theory of aging and DNA damage theory of aging [4,5]. Further, the infliction of insults on genomic DNA from intercalating agents, radiation, reactive oxygen species (ROS), and DNA double strand breaks have been reported to contribute to premature aging phenotypes in several mice models [6–8]. Additionally, in human progeroid syndrome HGPS, delayed recruitment of DNA-damage checkpoint response proteins has been established as a causative factor for accrued genomic instability [9]. Similarly, mutation/deletion of several genes has been shown to accelerate or delay aging process. For example, Sirt6-deficient mice display premature aging phenotypes accompanied with genomic instability [10]. Mutation in the Insulin/Insulin like growth factor (IGF1) receptor gene daf-2 has been reported to double the lifespan of C. elegans [11]. Also, mitochondrial DNA (mtDNA) mutations result in aging phenotypes in the mtDNA mutator mouse models [12]. Taken together, these studies clearly suggest a pivotal part played by genome maintenance and DNA damage repair in the process of cellular senescence and aging.
Progeroid syndromes: a genetic background http://dx.doi.org/10.1016/j.gde.2014.05.003 0959-437X/# 2014 Elsevier Ltd. All rights reserved.
Introduction Aging broadly refers to the gradual deterioration of physical and psychological abilities accompanied by a decline in the proper body functioning and resistance to the threats that an individual is exposed to. In the past few decades, this field has ignited interest in scientific communities especially because its underlying mechanisms began to be unveiled. Although several cellular pathways have emerged as key players in the process of biological aging, a significant proportion of them eventually converge as the threats being posed on genomic integrity [1,2]. The insults to genomic stability have further evolved as causative factor of several premature aging syndromes like Cockayne syndrome, Werner syndrome, HGPS and many more [3]. Here, we review the genetic alterations leading to progeroid syndromes (especially progeria) and other laminopathies. www.sciencedirect.com
Progeroid or premature aging syndromes are a class of rarely occurring genetic disorders. They can be broadly classified into unimodal progeroid syndromes (affecting only one tissue type) and segmental progeroid syndromes (affecting several tissues and displaying some but not all symptoms of normal physiological aging). Familial Alzheimer’s disease and Parkinson’s disease fall under the first category. The segmental progeroid syndromes largely comprise of monogenic disorders with malfunction arising from single gene mutations in the affected individuals. Some of the most widely studied examples are Cockayne syndrome, Werner syndrome, HGPS and Bloom’s syndrome. They can be further categorized into four groups based on the type of genes being mutated (Figure 1) [13–15]. However, the extrapolation of premature aging to physiological aging has often been debated since these syndromes recapitulate only a fraction of the alterations observed in normal aging process and hence might present highly specialized physiological conditions [16,17]. However, recent studies in HGPS have gained limelight in connecting premature aging to normal aging. The findings such as existence of progerin expression in normal individuals and increase in the level of progerin in the tissues of coronary arteries with gradual aging, further support this idea [18]. Current Opinion in Genetics & Development 2014, 26:41–46
42 Molecular and genetic bases of disease
Figure 1
Progeroid Syndromes (PS)
Unimodal Progeroid Syndrome
Alzheimer’s disease
Nucleotide excision repair (NER) genes
Segmental Progeroid Syndrome
Parkinson’s disease
RECQL mutated genes
LMNA/ZMPSTE24 mutated genes
Other DNA damage signaling genes
Xeroderma Pigmentosum
Bloom’s syndrome
Ataxia Telangiectasia mutated
Cockayne Syndrome
Werner syndrome
HutshinsonGilford Progeria syndrome
Trichothiodystrophy
Rothmund Thomson syndrome
Restrictive Dermopathy
Current Opinion in Genetics & Development
Categorization of progeroid syndromes: progeroid syndromes can be broadly classified on the basis of number and type of affected tissues and also on the type of genes mutated/deleted.
Progeria: underlying genetic mechanisms Hutchinson–Gilford progeria syndrome (HGPS) is a rare and severe early onset progeroid syndrome. It was first reported more than a century ago by Jonathan Hutchinson in 1886 and Hastings Gilford in 1897 independently (hence the name HGPS). It gained limelight in 2003 when its underlying genetic defect was discovered. Progeria is characterized predominantly by a unique heterozygous autosomal de novo point mutation in LMNA gene (C1824 T) which codes for the nuclear lamina protein lamin A [19,20]. The major nuclear lamin proteins expressed in humans are lamins A, C, B1, B2 and B3 encoded by the genes LMNA (for both lamins A and C), LMNB1 and LMNB2 (for both lamins B2 and B3), respectively [21]. These proteins form the only class of intermediate filament proteins in the nucleus which support the structure and shape of the nucleus, anchor chromatin and also tether nuclear pore complexes in their appropriate functional positions [22]. Lamin A (LA) is processed from its precursor prelamin A which contains a CaaX motif at its C terminal. This Cysteine residue undergoes farnesylation which leads to the cleavage of the aaX group followed by a methyl esterification of the Cysteine residue by isoprenylcysteine carboxyl methyltransferase (ICMT). This activates cleavage of an additional 15 amino acids of the precursor by the metalloproteinase, ZMPSTE24, to generate mature lamin A [23]. Current Opinion in Genetics & Development 2014, 26:41–46
In HGPS, a single base substitution (C1824T) in the LMNA gene activates a cryptic splice site within exon 11, giving rise to a 50 amino acids deleted prelamin A termed as Progerin that lacks the second cleavage (of 15 amino acids). This farnesylated progerin is considered toxic to the cells [19,20]. Many mouse models have been developed so far to study progeria, including Zmpste24 / mice, G608G BAC transgenic mice, Keratin 14-progerin transgenic mice, and Lmna G609G knock-in mice [24]. The pathology of progeria is attributable to several genetic defects (Figure 2) [25]. Some of them are described below.
Telomere dysfunction Aging has time and again been associated with accumulation of DNA lesions and defects in DNA damage repair mechanisms. Telomere shortening and dysfunction is a chief contributor to this DNA damage and poses serious threat to the integrity of genome [25]. Telomere attrition is also a major hallmark of aging and cellular senescence [26–29]. Mammalian telomeres essentially comprise of hexameric sequence repeats TTAGGG and the shelterin protein complex capping the telomere ends [30]. The telomeres shorten after each replication cycle as DNA polymerase cannot extend till its extreme end, thereby generating DNA-damage checkpoint response signaling. This eventually gets accrued on to elicit an irreversible www.sciencedirect.com
Chromatin remodeling defects in progeria Ghosh and Zhou 43
Figure 2
LMNA gene mutations
Telomere dysfunction
Altered gene-protein interactions
HutchinsonGilford progeria syndrome (HGPS)
Cellular phenotypes: Hterochromatin loss Nuclear lobulation Increased apoptosis Impaired DNA damage repair Mitochondrial dysfunction Cell-cycle regulation defects
Epigenetic alterations
Chromatin remodeling defects
Symptoms observed: Alopecia Atherosclerosis Cachexia Kidney failure Scleroderma Cardiovascular problems Current Opinion in Genetics & Development
Defective genetic pathways and consequences of HGPS: several defects in different genetic pathways contribute to the cellular malfunctions and severe symptoms observed in Hutchinson–Gilford Progeria Syndrome patients.
growth arrest, eventually resulting in senescence [31–33]. Recent studies suggest an inter-play between progerin accumulation and telomere dysfunction. In HGPS cells, it is reported that telomerase, a telomere-elongating ribonucleoprotein comprising a reverse transcriptase (TERT) and RNA component (TERC), extends cellular lifespan by toning down the DNA damage signaling triggered by progerin. In addition, progerin-induced DNA damage signaling is shown to concentrate in telomeres and majorly associate with telomere aggregates [34,35]. On the other hand, fibroblast clones from HGPS patients have shown to senesce even after reinstating telomere length and activity [36]. Taken together, the cause and effect of telomereprogerin relationship still remains largely elusive. Intriguingly, a recent publication demonstrated that lamin A Dexon9 mutation caused telomere and chromatin defects but did not result in genomic instability [37]. Thus the mechanistic link between telomere attrition, progerin accumulation and genomic instability and their interdependence on each other still needs further investigation to draw a more concrete conclusion.
Perturbed epigenetic regulation Epigenetic modifications like DNA methylation, acetylation, phosphorylation, and ubiquitylation, are known to www.sciencedirect.com
regulate the dynamics of chromatin organization. DNA methylation typically characterizes heterochromatin (the more transcriptionally silent form) while acetylated N-terminal histone tails promote euchromatin formation (the actively transcribing form) [38,39]. As observed in cellular senescence, HGPS fibroblasts also show marked decline in heterochromatin markers like histone H3 lysine 9 methylation (H3K9me) and HP1 proteins that further decrease with passage [40–42]. Interestingly, our recent data demonstrated an increase in H3K9 trimethylation in Zmpste24 / cells due to elevation in SUV39H1 (methyltransferase responsible for H3K9me3) levels [43]. This discrepancy was attributable to the difference in passage numbers of the primary human cells used in experimentation as perfectly matched wildtype primary dermal fibroblasts are unlikely to be obtained. To this end, data from mice are more reliable. Our data established that SUV39H1 depletion could partially alleviate DNA damage repair and delay senescence in progeroid cells. Other epigenetic modifications like downregulated H3K27 trimethylation and upregulated H4K20 trimethylation have also been reported in HGPS cells [44,45]. Our previous report also identified H4K16 hypoacetylation in Zmpste24 / mice [46]. In addition, we showed that decrease in H4K16 acetylation could also be observed in Current Opinion in Genetics & Development 2014, 26:41–46
44 Molecular and genetic bases of disease
normally aging cells. This epigenetic modification led to improper recruitment of damage repair proteins to DNA lesions. Treatment of the mutant mice with HDAC inhibitor, Sodium Butyrate (NaB), restored the acetylation level of H4 and partially rescued the progeroid features in mice. This finding provides a novel therapeutic strategy for progeria. On the whole, these reports suggest that targeting epigenetic modifiers can have potential benefits in the intervention of premature aging.
Chromatin remodeling: an emerging player in premature aging A plethora of ATP-dependent or covalently modifying remodeling factors largely regulates chromatin structure and compaction that determines DNA accessibility to several chromatin-associated factors required for DNA replication, transcription and damage repair. The identification of NURD (Nucleosome Remodeling Deacetylase) complex’s pivotal role in aging further strengthened this idea [47]. NURD is a chromatin remodeling complex containing seven subunits which primarily function in histone deacetylation and methyl-CpG binding [48]. HGPS cells as well as normally aged cells show decline in several NURD components like HDAC1 and histone chaperones RBBP4. It is also reported that knockdown of NURD components reiterates chromatin defects and DNA damage observed in aging [47]. Similarly, histone H4K20 methylase SET8 has also been demonstrated to elevate DNA damage when depleted in normal cells [49]. In addition to these, our recent study identified defective ATM-Kap1 signaling as a major contributor to DNA damage repair defects observed in Zmpste24 / MEFs (mouse embryonic fibroblasts). We also showed that Kap1 knockdown could rescue those defects along with chromatin remodeling impairments and delay senescence in the mutant MEFs [50]. Recently, it has also been reported that decreased ICMT activity resulted in prelamin A mislocalization, causing enhanced AKT- mammalian target of rapamycin (mTOR) signaling and delayed senescence in HGPS fibroblasts [51]. Apart from these, our research on mammalian sirtuin SIRT1 (class III histone deacetylase and mono-ADP ribosyltransferase) has yielded very promising results and provided a novel mechanistic explanation to resveratrol’s anti-aging effects [52]. Taken together, the above findings clearly advocate a promising role for the chromatin modifiers in understanding the intricate molecular mechanisms underlying premature senescence.
Altered protein interactions It is reported that progerin elicits chromatin organization changes globally by increasing interactions with a specific subset of genes in addition to those that are associated with lamin A [53]. In addition, the inner nuclear membrane protein SUN1 is observed to over-accumulate in HGPS cells and LMNA mutant fibroblasts. Minimizing this over-accumulation ameliorated nuclear defects and Current Opinion in Genetics & Development 2014, 26:41–46
cellular senescence [54]. Several such protein interaction defects have been reported which also partly explain the pathology of progeria. For example, altered interaction in between lamin A/progerin and various transcription factors like PRX1, MEOX/GAX, TWIST2, have been described to contribute to progeroid phenotypes [25].
Atypical HGPS conditions Apart from the known heterozygous point mutation C1824 T observed in classical HGPS, two recent reports described that a C1579 T missense mutation in exon 9 results in R527 C substitution causing progeria [55,56]. This homozygous mutation caused several typical HGPS phenotypes in the patients along with digestive system disorders and more severe skeletal damage. In both cases, the siblings were homozygous while their parents were heterozygous for this mutation. In addition, three different substitutions at the 527 coding site in LMNA gene viz. R527P, R527H and R527C/R471C cause different disorders like Emery–Dreifuss Muscular dystrophy and mandibuloacral dysplasia [56]. Intriguingly, homozygous mutation G1626G, that is p.K542N affecting both lamins A and C is also observed to cause HGPS [57]. This study challenged the concept of only lamin A mutations to be responsible for causing HGPS. Another report revealed an additional heterozygous mutation in LMNA gene G1821A causing neonatal progeria [58]. These reports are thus suggestive of the existence of varied forms of point mutations in LMNA gene that can also result in progeroid phenotypes.
Other lamin disorders Till date, nearly 15 disorders have been attributed to LMNA mutations. These disorders arising from defects in nuclear lamin genes are collectively termed as laminopathies. Apart from the accelerated aging syndromes like HGPS, atypical Werner syndrome, and Restrictive dermopathy (also caused by loss of ZMPSTE24 gene), lamin related disorders also encompass several striated muscle diseases, peripheral nerve disorders, lipodystrophy, and bone diseases [59]. LMNA gene mutations like Emery– Dreifuss muscular dystrophy and Limb-girdle muscular dystrophy also result in dilated cardiomyopathy which causes mortality. Apart from these, deletion mutation in ZMPSTE24 gene results in partially mature lamin A and causes Mandibuloacral dysplasia and Restrictive dermopathy. Furthermore, homozygous loss of lamin A function results in peripheral nerve myelination loss, thereby causing Charcot–Marie tooth syndrome. Mutations in LMNB1 and LMNB2 also result in adult-onset lipodystrophy and partial lipodystrophy respectively. In addition, homozygous and heterozygous mutations in the lamin B receptor (LBR) cause Greenberg skeletal dysplasia and Pelger–Huet anomaly respectively [60]. This whole spectrum of laminopathies clearly indicates the significance of nuclear lamin genes in maintaining genomic integrity and proper cellular functioning. www.sciencedirect.com
Chromatin remodeling defects in progeria Ghosh and Zhou 45
Discussion So far, there have been numerous studies highlighting the importance of genetics in the field of premature aging related disorders. With upcoming reports on several gene functions, the genetic mechanisms underlying these disorders are becoming clearer. Several novel studies are being carried out in order that not only lifespan but also healthspan of individuals could be enhanced. However, the complications associated with progeria are numerous making it more challenging to devise one solution for targeting all of them. But, with the advent of several promising genetic approaches, it is expected that an effective therapy could be devised to ameliorate the severe progeroid phenotypes observed in patients.
Acknowledgements We would like to acknowledge the supports from National Natural Science Foundation of China (81330009), Chinese Ministry of Science and Technology (973 Project 2011CB964700), and Hong Kong Research Council CRF (HKU2/CRF/13G).
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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ScienceDirect Genetics of aging, progeria and lamin disorders Shrestha Ghosh1 and Zhongjun Zhou1,2 Premature aging disorders, like Werner syndrome, Bloom’s syndrome, and Hutchinson–Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways involved in the maintenance of genomic integrity, thus suggesting a profound impact of the nuclear lamina in nuclear organization, chromatin dynamics, regulation of gene expression and epigenetics. Addresses 1 Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 2 Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China Corresponding author: Zhou, Zhongjun ([email protected])
Current Opinion in Genetics & Development 2014, 26:41–46 This review comes from a themed issue on Molecular and genetic bases of disease Edited by Cynthia T McMurray and Jan Vijg
Physiological and premature aging: from the perspective of genetics The prominence of genetic contribution to aging was primarily advocated by two theories, somatic mutation theory of aging and DNA damage theory of aging [4,5]. Further, the infliction of insults on genomic DNA from intercalating agents, radiation, reactive oxygen species (ROS), and DNA double strand breaks have been reported to contribute to premature aging phenotypes in several mice models [6–8]. Additionally, in human progeroid syndrome HGPS, delayed recruitment of DNA-damage checkpoint response proteins has been established as a causative factor for accrued genomic instability [9]. Similarly, mutation/deletion of several genes has been shown to accelerate or delay aging process. For example, Sirt6-deficient mice display premature aging phenotypes accompanied with genomic instability [10]. Mutation in the Insulin/Insulin like growth factor (IGF1) receptor gene daf-2 has been reported to double the lifespan of C. elegans [11]. Also, mitochondrial DNA (mtDNA) mutations result in aging phenotypes in the mtDNA mutator mouse models [12]. Taken together, these studies clearly suggest a pivotal part played by genome maintenance and DNA damage repair in the process of cellular senescence and aging.
Progeroid syndromes: a genetic background http://dx.doi.org/10.1016/j.gde.2014.05.003 0959-437X/# 2014 Elsevier Ltd. All rights reserved.
Introduction Aging broadly refers to the gradual deterioration of physical and psychological abilities accompanied by a decline in the proper body functioning and resistance to the threats that an individual is exposed to. In the past few decades, this field has ignited interest in scientific communities especially because its underlying mechanisms began to be unveiled. Although several cellular pathways have emerged as key players in the process of biological aging, a significant proportion of them eventually converge as the threats being posed on genomic integrity [1,2]. The insults to genomic stability have further evolved as causative factor of several premature aging syndromes like Cockayne syndrome, Werner syndrome, HGPS and many more [3]. Here, we review the genetic alterations leading to progeroid syndromes (especially progeria) and other laminopathies. www.sciencedirect.com
Progeroid or premature aging syndromes are a class of rarely occurring genetic disorders. They can be broadly classified into unimodal progeroid syndromes (affecting only one tissue type) and segmental progeroid syndromes (affecting several tissues and displaying some but not all symptoms of normal physiological aging). Familial Alzheimer’s disease and Parkinson’s disease fall under the first category. The segmental progeroid syndromes largely comprise of monogenic disorders with malfunction arising from single gene mutations in the affected individuals. Some of the most widely studied examples are Cockayne syndrome, Werner syndrome, HGPS and Bloom’s syndrome. They can be further categorized into four groups based on the type of genes being mutated (Figure 1) [13–15]. However, the extrapolation of premature aging to physiological aging has often been debated since these syndromes recapitulate only a fraction of the alterations observed in normal aging process and hence might present highly specialized physiological conditions [16,17]. However, recent studies in HGPS have gained limelight in connecting premature aging to normal aging. The findings such as existence of progerin expression in normal individuals and increase in the level of progerin in the tissues of coronary arteries with gradual aging, further support this idea [18]. Current Opinion in Genetics & Development 2014, 26:41–46
42 Molecular and genetic bases of disease
Figure 1
Progeroid Syndromes (PS)
Unimodal Progeroid Syndrome
Alzheimer’s disease
Nucleotide excision repair (NER) genes
Segmental Progeroid Syndrome
Parkinson’s disease
RECQL mutated genes
LMNA/ZMPSTE24 mutated genes
Other DNA damage signaling genes
Xeroderma Pigmentosum
Bloom’s syndrome
Ataxia Telangiectasia mutated
Cockayne Syndrome
Werner syndrome
HutshinsonGilford Progeria syndrome
Trichothiodystrophy
Rothmund Thomson syndrome
Restrictive Dermopathy
Current Opinion in Genetics & Development
Categorization of progeroid syndromes: progeroid syndromes can be broadly classified on the basis of number and type of affected tissues and also on the type of genes mutated/deleted.
Progeria: underlying genetic mechanisms Hutchinson–Gilford progeria syndrome (HGPS) is a rare and severe early onset progeroid syndrome. It was first reported more than a century ago by Jonathan Hutchinson in 1886 and Hastings Gilford in 1897 independently (hence the name HGPS). It gained limelight in 2003 when its underlying genetic defect was discovered. Progeria is characterized predominantly by a unique heterozygous autosomal de novo point mutation in LMNA gene (C1824 T) which codes for the nuclear lamina protein lamin A [19,20]. The major nuclear lamin proteins expressed in humans are lamins A, C, B1, B2 and B3 encoded by the genes LMNA (for both lamins A and C), LMNB1 and LMNB2 (for both lamins B2 and B3), respectively [21]. These proteins form the only class of intermediate filament proteins in the nucleus which support the structure and shape of the nucleus, anchor chromatin and also tether nuclear pore complexes in their appropriate functional positions [22]. Lamin A (LA) is processed from its precursor prelamin A which contains a CaaX motif at its C terminal. This Cysteine residue undergoes farnesylation which leads to the cleavage of the aaX group followed by a methyl esterification of the Cysteine residue by isoprenylcysteine carboxyl methyltransferase (ICMT). This activates cleavage of an additional 15 amino acids of the precursor by the metalloproteinase, ZMPSTE24, to generate mature lamin A [23]. Current Opinion in Genetics & Development 2014, 26:41–46
In HGPS, a single base substitution (C1824T) in the LMNA gene activates a cryptic splice site within exon 11, giving rise to a 50 amino acids deleted prelamin A termed as Progerin that lacks the second cleavage (of 15 amino acids). This farnesylated progerin is considered toxic to the cells [19,20]. Many mouse models have been developed so far to study progeria, including Zmpste24 / mice, G608G BAC transgenic mice, Keratin 14-progerin transgenic mice, and Lmna G609G knock-in mice [24]. The pathology of progeria is attributable to several genetic defects (Figure 2) [25]. Some of them are described below.
Telomere dysfunction Aging has time and again been associated with accumulation of DNA lesions and defects in DNA damage repair mechanisms. Telomere shortening and dysfunction is a chief contributor to this DNA damage and poses serious threat to the integrity of genome [25]. Telomere attrition is also a major hallmark of aging and cellular senescence [26–29]. Mammalian telomeres essentially comprise of hexameric sequence repeats TTAGGG and the shelterin protein complex capping the telomere ends [30]. The telomeres shorten after each replication cycle as DNA polymerase cannot extend till its extreme end, thereby generating DNA-damage checkpoint response signaling. This eventually gets accrued on to elicit an irreversible www.sciencedirect.com
Chromatin remodeling defects in progeria Ghosh and Zhou 43
Figure 2
LMNA gene mutations
Telomere dysfunction
Altered gene-protein interactions
HutchinsonGilford progeria syndrome (HGPS)
Cellular phenotypes: Hterochromatin loss Nuclear lobulation Increased apoptosis Impaired DNA damage repair Mitochondrial dysfunction Cell-cycle regulation defects
Epigenetic alterations
Chromatin remodeling defects
Symptoms observed: Alopecia Atherosclerosis Cachexia Kidney failure Scleroderma Cardiovascular problems Current Opinion in Genetics & Development
Defective genetic pathways and consequences of HGPS: several defects in different genetic pathways contribute to the cellular malfunctions and severe symptoms observed in Hutchinson–Gilford Progeria Syndrome patients.
growth arrest, eventually resulting in senescence [31–33]. Recent studies suggest an inter-play between progerin accumulation and telomere dysfunction. In HGPS cells, it is reported that telomerase, a telomere-elongating ribonucleoprotein comprising a reverse transcriptase (TERT) and RNA component (TERC), extends cellular lifespan by toning down the DNA damage signaling triggered by progerin. In addition, progerin-induced DNA damage signaling is shown to concentrate in telomeres and majorly associate with telomere aggregates [34,35]. On the other hand, fibroblast clones from HGPS patients have shown to senesce even after reinstating telomere length and activity [36]. Taken together, the cause and effect of telomereprogerin relationship still remains largely elusive. Intriguingly, a recent publication demonstrated that lamin A Dexon9 mutation caused telomere and chromatin defects but did not result in genomic instability [37]. Thus the mechanistic link between telomere attrition, progerin accumulation and genomic instability and their interdependence on each other still needs further investigation to draw a more concrete conclusion.
Perturbed epigenetic regulation Epigenetic modifications like DNA methylation, acetylation, phosphorylation, and ubiquitylation, are known to www.sciencedirect.com
regulate the dynamics of chromatin organization. DNA methylation typically characterizes heterochromatin (the more transcriptionally silent form) while acetylated N-terminal histone tails promote euchromatin formation (the actively transcribing form) [38,39]. As observed in cellular senescence, HGPS fibroblasts also show marked decline in heterochromatin markers like histone H3 lysine 9 methylation (H3K9me) and HP1 proteins that further decrease with passage [40–42]. Interestingly, our recent data demonstrated an increase in H3K9 trimethylation in Zmpste24 / cells due to elevation in SUV39H1 (methyltransferase responsible for H3K9me3) levels [43]. This discrepancy was attributable to the difference in passage numbers of the primary human cells used in experimentation as perfectly matched wildtype primary dermal fibroblasts are unlikely to be obtained. To this end, data from mice are more reliable. Our data established that SUV39H1 depletion could partially alleviate DNA damage repair and delay senescence in progeroid cells. Other epigenetic modifications like downregulated H3K27 trimethylation and upregulated H4K20 trimethylation have also been reported in HGPS cells [44,45]. Our previous report also identified H4K16 hypoacetylation in Zmpste24 / mice [46]. In addition, we showed that decrease in H4K16 acetylation could also be observed in Current Opinion in Genetics & Development 2014, 26:41–46
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normally aging cells. This epigenetic modification led to improper recruitment of damage repair proteins to DNA lesions. Treatment of the mutant mice with HDAC inhibitor, Sodium Butyrate (NaB), restored the acetylation level of H4 and partially rescued the progeroid features in mice. This finding provides a novel therapeutic strategy for progeria. On the whole, these reports suggest that targeting epigenetic modifiers can have potential benefits in the intervention of premature aging.
Chromatin remodeling: an emerging player in premature aging A plethora of ATP-dependent or covalently modifying remodeling factors largely regulates chromatin structure and compaction that determines DNA accessibility to several chromatin-associated factors required for DNA replication, transcription and damage repair. The identification of NURD (Nucleosome Remodeling Deacetylase) complex’s pivotal role in aging further strengthened this idea [47]. NURD is a chromatin remodeling complex containing seven subunits which primarily function in histone deacetylation and methyl-CpG binding [48]. HGPS cells as well as normally aged cells show decline in several NURD components like HDAC1 and histone chaperones RBBP4. It is also reported that knockdown of NURD components reiterates chromatin defects and DNA damage observed in aging [47]. Similarly, histone H4K20 methylase SET8 has also been demonstrated to elevate DNA damage when depleted in normal cells [49]. In addition to these, our recent study identified defective ATM-Kap1 signaling as a major contributor to DNA damage repair defects observed in Zmpste24 / MEFs (mouse embryonic fibroblasts). We also showed that Kap1 knockdown could rescue those defects along with chromatin remodeling impairments and delay senescence in the mutant MEFs [50]. Recently, it has also been reported that decreased ICMT activity resulted in prelamin A mislocalization, causing enhanced AKT- mammalian target of rapamycin (mTOR) signaling and delayed senescence in HGPS fibroblasts [51]. Apart from these, our research on mammalian sirtuin SIRT1 (class III histone deacetylase and mono-ADP ribosyltransferase) has yielded very promising results and provided a novel mechanistic explanation to resveratrol’s anti-aging effects [52]. Taken together, the above findings clearly advocate a promising role for the chromatin modifiers in understanding the intricate molecular mechanisms underlying premature senescence.
Altered protein interactions It is reported that progerin elicits chromatin organization changes globally by increasing interactions with a specific subset of genes in addition to those that are associated with lamin A [53]. In addition, the inner nuclear membrane protein SUN1 is observed to over-accumulate in HGPS cells and LMNA mutant fibroblasts. Minimizing this over-accumulation ameliorated nuclear defects and Current Opinion in Genetics & Development 2014, 26:41–46
cellular senescence [54]. Several such protein interaction defects have been reported which also partly explain the pathology of progeria. For example, altered interaction in between lamin A/progerin and various transcription factors like PRX1, MEOX/GAX, TWIST2, have been described to contribute to progeroid phenotypes [25].
Atypical HGPS conditions Apart from the known heterozygous point mutation C1824 T observed in classical HGPS, two recent reports described that a C1579 T missense mutation in exon 9 results in R527 C substitution causing progeria [55,56]. This homozygous mutation caused several typical HGPS phenotypes in the patients along with digestive system disorders and more severe skeletal damage. In both cases, the siblings were homozygous while their parents were heterozygous for this mutation. In addition, three different substitutions at the 527 coding site in LMNA gene viz. R527P, R527H and R527C/R471C cause different disorders like Emery–Dreifuss Muscular dystrophy and mandibuloacral dysplasia [56]. Intriguingly, homozygous mutation G1626G, that is p.K542N affecting both lamins A and C is also observed to cause HGPS [57]. This study challenged the concept of only lamin A mutations to be responsible for causing HGPS. Another report revealed an additional heterozygous mutation in LMNA gene G1821A causing neonatal progeria [58]. These reports are thus suggestive of the existence of varied forms of point mutations in LMNA gene that can also result in progeroid phenotypes.
Other lamin disorders Till date, nearly 15 disorders have been attributed to LMNA mutations. These disorders arising from defects in nuclear lamin genes are collectively termed as laminopathies. Apart from the accelerated aging syndromes like HGPS, atypical Werner syndrome, and Restrictive dermopathy (also caused by loss of ZMPSTE24 gene), lamin related disorders also encompass several striated muscle diseases, peripheral nerve disorders, lipodystrophy, and bone diseases [59]. LMNA gene mutations like Emery– Dreifuss muscular dystrophy and Limb-girdle muscular dystrophy also result in dilated cardiomyopathy which causes mortality. Apart from these, deletion mutation in ZMPSTE24 gene results in partially mature lamin A and causes Mandibuloacral dysplasia and Restrictive dermopathy. Furthermore, homozygous loss of lamin A function results in peripheral nerve myelination loss, thereby causing Charcot–Marie tooth syndrome. Mutations in LMNB1 and LMNB2 also result in adult-onset lipodystrophy and partial lipodystrophy respectively. In addition, homozygous and heterozygous mutations in the lamin B receptor (LBR) cause Greenberg skeletal dysplasia and Pelger–Huet anomaly respectively [60]. This whole spectrum of laminopathies clearly indicates the significance of nuclear lamin genes in maintaining genomic integrity and proper cellular functioning. www.sciencedirect.com
Chromatin remodeling defects in progeria Ghosh and Zhou 45
Discussion So far, there have been numerous studies highlighting the importance of genetics in the field of premature aging related disorders. With upcoming reports on several gene functions, the genetic mechanisms underlying these disorders are becoming clearer. Several novel studies are being carried out in order that not only lifespan but also healthspan of individuals could be enhanced. However, the complications associated with progeria are numerous making it more challenging to devise one solution for targeting all of them. But, with the advent of several promising genetic approaches, it is expected that an effective therapy could be devised to ameliorate the severe progeroid phenotypes observed in patients.
Acknowledgements We would like to acknowledge the supports from National Natural Science Foundation of China (81330009), Chinese Ministry of Science and Technology (973 Project 2011CB964700), and Hong Kong Research Council CRF (HKU2/CRF/13G).
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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