Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome.
Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome.
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DOI：
10.1016/j.tig.2015.05.009
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
van Ravenswaaij-Arts C
中科院分区：
文献类型：
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作者：
Basson MA;van Ravenswaaij-Arts C
CHARGE综合征是一种罕见的遗传综合征，其特征是多器官异常的独特组合。编码染色体结构解旋酶DNA结合蛋白7 （CHD7）的基因的显性功能缺失突变，是一种依赖于atp的染色质重塑剂，已被确定为CHARGE综合征的原因。在这里，我们回顾了最近的工作，旨在了解CHD7在正常和病理状态下的功能机制，重点介绍了生化和体内研究的结果。这项工作的新结果表明，CHD7微调基因表达的机制是特定于环境的，与CHARGE综合征的多效性一致。CHARGE表型的表达率和外显率与CHD7基因型的相关性不大。其他基因的突变或多态性改变人类疾病表型的假设仍未得到证实。电荷相关的CHD7突变可以影响其体外核小体重塑活性。CHD7在体内调节核小体定位中的作用及其对基因表达的影响有待进一步研究。CHD7多效性可能是由于它与细胞类型特异性转录因子的相互作用。细胞类型特异性增强子的CHD7募集可能是环境特异性作用的基础。
CHARGE syndrome is a rare genetic syndrome characterised by a unique combination of multiple organ anomalies. Dominant loss-of-function mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is an ATP-dependent chromatin remodeller, have been identified as the cause of CHARGE syndrome. Here, we review recent work aimed at understanding the mechanism of CHD7 function in normal and pathological states, highlighting results from biochemical and in vivo studies. The emerging picture from this work suggests that the mechanisms by which CHD7 fine-tunes gene expression are context specific, consistent with the pleiotropic nature of CHARGE syndrome. The expressivity and penetrance of CHARGE phenotypes show little correlation with the CHD7 genotype. The hypothesis that mutations or polymorphisms in other genes modify disease phenotypes in humans remains unproven. CHARGE-associated CHD7 mutations can affect its nucleosome remodelling activity in vitro. The role of CHD7 in regulating nucleosome positioning in vivo and the effects of this activity on gene expression require further study. CHD7 pleiotropy may result from its interactions with cell type-specific transcription factors. CHD7 recruitment to cell type-specific enhancers may underlie context-specific roles.