Heterochromatin as an incubator for pathology and treatment non-response: implication for neuropsychiatric illness.
Heterochromatin as an incubator for pathology and treatment non-response: implication for neuropsychiatric illness.
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DOI：
10.1038/tpj.2011.64
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Chase KA
中科院分区：
文献类型：
--
作者：
Sharma RP;Gavin DP;Chase KA
异染色质是一种高阶组装体，其特征在于全基因组分布、基因抑制、持久性和扩散潜力。在这种情况下，这是一个有吸引力的机制来解释复杂的大脑疾病，如精神分裂症，其中表达下调似乎是正常的神经生物学。H3K9甲基化（H3K9me）可以启动异染色质组装在失活或协调不良的启动子上的播种，这是由于反式激活因子因废弃或误用而下降的结果。H3K9me可以通过递归募集衔接子（如HP 1同源二聚体）的机制通过空间扩散来扩展其影响。HP1本身是其他抑制蛋白如DNA甲基转移酶的平台。在全色中，异染色质可以占据全基因组的基因网络，组织特异性本体，甚至重新排列核结构。大脑中的异染色质通过小分子药理学进行修饰，并在多巴胺神经元的功能和记忆的构建中发挥生理作用。从治疗的角度来看，异染色质的持久性意味着在实现标准药物疗法的全部基因组潜力之前，它可能需要拆卸，特别是在治疗抗性患者中。
Heterochromatin is a higher order assembly that is characterized by a genomewide distribution, gene-repression, durability, and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where down-regulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters such as HP1 homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genomewide gene networks, tissue specific ontologies, and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology, and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic-potential of standard pharmacotherapies is achieved, especially in treatment resistant patients.
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