Epigenetics of Schizophrenia
Epigenetics of Schizophrenia
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DOI：
10.1007/7854_2010_38
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发表时间：
2010-01-01
期刊：
影响因子：
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通讯作者：
Akbarian, Schahram
中科院分区：
文献类型：
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作者：
Akbarian, Schahram
基因表达的表观遗传调节，包括DNA胞嘧啶甲基化和翻译后组蛋白修饰，可能在精神分裂症相关的一些分子变化中发挥作用。例如，在精神分裂症受试者的前额叶皮质中，特定基因和启动子位置的DNA或组蛋白甲基化异常与RNA表达的变化有关。从神经发育的角度来看，这些发现令人感兴趣，因为越来越多的证据表明，相当大一部分基因和基因座的表观遗传标记在生命的头几年受到高度调控。此外，有间接证据表明，抗精神病药物的一部分，包括非典型的氯氮平，干扰染色质重塑机制。该领域面临的挑战包括：(1)对于疾病相关的变化尚无明确的共识，(2)缺乏细胞特异性染色质分析，这使得很难将表观遗传变化归因于特定的细胞群体，以及(3)缺乏关于(大脑)染色质特定位置的表观遗传标记的稳定性或更替的知识。尽管有这些缺点，但对从患病和对照脑组织中提取的染色质中DNA和组蛋白修饰的研究可能会为精神分裂症的基因组风险架构提供宝贵的见解，特别是在绝大多数病例中，直接的遗传原因仍然难以找到。
Epigenetic regulators of gene expression including DNA cytosine methylation and posttranslational histone modifications could play a role for some of the molecular alterations associated with schizophrenia. For example, in prefrontal cortex of subjects with schizophrenia, abnormal DNA or histone methylation at sites of specific genes and promoters is associated with changes in RNA expression. These findings are of interest from a neurodevelopmental perspective because there is increasing evidence that epigenetic markings for a substantial portion of genes and loci are highly regulated during the first years of life. Furthermore, there is circumstantial evidence that a subset of antipsychotic drugs, including the atypical, Clozapine, interfere with chromatin remodeling mechanisms. Challenges for the field include (1) no clear consensus yet regarding disease-associated changes, (2) the lack of cell-specific chromatin assays which makes it difficult to ascribe epigenetic alterations to specific cell populations, and (3) lack of knowledge about the stability or turnover of epigenetic markings at specific loci in (brain) chromatin. Despite these shortcomings, the study of DNA and histone modifications in chromatin extracted from diseased and control brain tissue is likely to provide valuable insight into the genomic risk architecture of schizophrenia, particularly in the large majority of cases for which a straightforward genetic cause still remains elusive.