- Email: [email protected]
Behavioural epigenetics and psychiatric disorders
Correspondence
453
Behavioural epigenetics and psychiatric disorders A rapidly emerging trend in neuroscience is one of linking ‘‘epigenetics’’ with gene expression and subsequent behaviour through a regulatory mechanism, traditionally restricted to developmental biology, known as chromatin remodeling. The idea that the central nervous system has co-opted this ancient, yet evolutionarily-conserved mechanism of cellular memory, and applied it to the formation and maintenance of long-term changes in behaviour is utterly mind-boggling, yet recent reports demonstrate that it is entirely conceivable [1,2]. At the heart of the story is the chromatin structure, the physiological substrate for all genetic activity within the nucleus of eukaryotic cells. Dynamic changes in chromatin structure are emerging as key regulators of tissue-specific gene expression associated with not only learning and memory, but also neuropsychiatric disorders such as schizophrenia, depression and addiction [3–5]. In particular, histone acetylation/deacetylation or dimethylation of nucleosomal histone proteins (i.e. H3–K9) and DNA methylation of CpG dinucleotides within gene promoter regions are two ways chromatin remodeling can influence ongoing transcription and synaptic plasticity. Covalent modification of histone proteins that lead to activation or repression of gene transcription are mediated by specific enzymes (i.e. histone deacetylase, HDAC), and the tissue specificity of these enzymes could make them potential therapeutic targets for the treatment of a myriad of neuropsychiatric disorders. The beauty of the approach is that one could conceivably bypass the task of determining the many neurochemical and molecular players associated with a given behaviour by taking advantage of this fundamental mechanism of gene regulation and targeting the chromatin structure itself, a sort of ‘‘inside-out’’ approach, if you will. For example, HDAC5 appears
to be preferentially expressed in the hippocampal formation and has recently been shown to play a role in depression-like behaviour [5]. Elucidating the entire biochemical process is not necessary when the target is the basic mechanism that regulates the expression of all genes activated by the behaviour in question. While advances are being made in the development of region and tissuespecific HDAC inhibitors, the current prototypical HDAC inhibitors (i.e. valproic acid and sodium butyrate) can still provide much needed information regarding the role of chromatin remodeling and its relationship with different forms of behaviour. In any case, if the story holds up, this ‘‘Occam’s razor’’ approach to the relationship between the epigenetic regulation of gene expression and behaviour could very well change the way we think about neuropsychiatric disorders and how memories are sustained at the level of the genome.
References [1] Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, et al. J Neurosci 2005;25(47):11045–54. [2] Levenson JM, Sweatt JD. Cell Mol Life Sci 2006;63(9): 1009–16. [3] Sharma RP. Schizophr Res 2005;72:79–90. [4] Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Nat Neurosci 2006;9(4):519–25. [5] Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, et al. Neuron 2005;48:303–14.
Timothy W. Bredy UCLA, 635 Charles E. Young Dr. South, NRB555E, Los Angeles, CA 90095, United States Tel.: +1 310 794 7331. E-mail address: [email protected].
doi:10.1016/j.mehy.2006.07.009
Asymmetric somatic stem cells division plays a critical role in cell senescence It is well known that the predominant kinetic state of somatic stem cells (SMCs) in vivo is an asymmetric division program. At each asymmet-
ric cell division, SMCs selectively retain a set of chromosomes that contain immortal DNA strands, which might contribute to stem cell self-renewal,
453
Behavioural epigenetics and psychiatric disorders A rapidly emerging trend in neuroscience is one of linking ‘‘epigenetics’’ with gene expression and subsequent behaviour through a regulatory mechanism, traditionally restricted to developmental biology, known as chromatin remodeling. The idea that the central nervous system has co-opted this ancient, yet evolutionarily-conserved mechanism of cellular memory, and applied it to the formation and maintenance of long-term changes in behaviour is utterly mind-boggling, yet recent reports demonstrate that it is entirely conceivable [1,2]. At the heart of the story is the chromatin structure, the physiological substrate for all genetic activity within the nucleus of eukaryotic cells. Dynamic changes in chromatin structure are emerging as key regulators of tissue-specific gene expression associated with not only learning and memory, but also neuropsychiatric disorders such as schizophrenia, depression and addiction [3–5]. In particular, histone acetylation/deacetylation or dimethylation of nucleosomal histone proteins (i.e. H3–K9) and DNA methylation of CpG dinucleotides within gene promoter regions are two ways chromatin remodeling can influence ongoing transcription and synaptic plasticity. Covalent modification of histone proteins that lead to activation or repression of gene transcription are mediated by specific enzymes (i.e. histone deacetylase, HDAC), and the tissue specificity of these enzymes could make them potential therapeutic targets for the treatment of a myriad of neuropsychiatric disorders. The beauty of the approach is that one could conceivably bypass the task of determining the many neurochemical and molecular players associated with a given behaviour by taking advantage of this fundamental mechanism of gene regulation and targeting the chromatin structure itself, a sort of ‘‘inside-out’’ approach, if you will. For example, HDAC5 appears
to be preferentially expressed in the hippocampal formation and has recently been shown to play a role in depression-like behaviour [5]. Elucidating the entire biochemical process is not necessary when the target is the basic mechanism that regulates the expression of all genes activated by the behaviour in question. While advances are being made in the development of region and tissuespecific HDAC inhibitors, the current prototypical HDAC inhibitors (i.e. valproic acid and sodium butyrate) can still provide much needed information regarding the role of chromatin remodeling and its relationship with different forms of behaviour. In any case, if the story holds up, this ‘‘Occam’s razor’’ approach to the relationship between the epigenetic regulation of gene expression and behaviour could very well change the way we think about neuropsychiatric disorders and how memories are sustained at the level of the genome.
References [1] Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, et al. J Neurosci 2005;25(47):11045–54. [2] Levenson JM, Sweatt JD. Cell Mol Life Sci 2006;63(9): 1009–16. [3] Sharma RP. Schizophr Res 2005;72:79–90. [4] Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Nat Neurosci 2006;9(4):519–25. [5] Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, et al. Neuron 2005;48:303–14.
Timothy W. Bredy UCLA, 635 Charles E. Young Dr. South, NRB555E, Los Angeles, CA 90095, United States Tel.: +1 310 794 7331. E-mail address: [email protected].
doi:10.1016/j.mehy.2006.07.009
Asymmetric somatic stem cells division plays a critical role in cell senescence It is well known that the predominant kinetic state of somatic stem cells (SMCs) in vivo is an asymmetric division program. At each asymmet-
ric cell division, SMCs selectively retain a set of chromosomes that contain immortal DNA strands, which might contribute to stem cell self-renewal,