Implications of Dosage Deficiencies in CTCF and Cohesin on Genome Organization, Gene Expression, and Human Neurodevelopment.
Implications of Dosage Deficiencies in CTCF and Cohesin on Genome Organization, Gene Expression, and Human Neurodevelopment.
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DOI：
10.3390/genes13040583
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发表时间：
2022-03-25
期刊：
影响因子：
3.5
通讯作者：
Rowley, M. Jordan
中科院分区：
文献类型：
--
作者：
Cummings, Christopher T.;Rowley, M. Jordan
细胞核内正确组织 DNA 对于确保正常的下游核功能至关重要。 CTCF 和粘连蛋白是主要的结构蛋白，协同作用产生数千个高强度染色质环。由于它们在环形成中的核心作用，大量的研究工作致力于研究 CTCF 和粘连蛋白创建这些环的机制。最近的结果引发了人们对 CTCF 环对基因表达的直接影响的质疑。此外，细胞系中受控耗竭实验的结果表明，基因组结构可能对 CTCF 或粘连蛋白的不完全缺陷有一定的抵抗力。然而，CTCF 和粘连蛋白的杂合人类遗传缺陷已经说明了它们的剂量在基因组结构、细胞过程、动物行为和疾病表型中的重要性。因此，这些表征遗传综合征的杂合种系变异尤其清楚地表明了考虑 CTCF 或粘连蛋白水平的重要性，这些变异在临床实践中越来越得到认可。 CTCF 和粘连蛋白缺乏的表型主要由发育迟缓和智力障碍定义，说明了结构蛋白的重要性，特别是在神经发育中。我们讨论了 CTCF 和粘连蛋白在形成染色质环中的独特作用，强调了每种蛋白质的剂量在观察到的基因表达影响幅度中所起的主要作用，并将这些结果与小鼠模型和临床患者的杂合突变表型进行对比。这种比较所强调的见解对这些新出现的遗传综合征的未来研究具有重要意义。
Properly organizing DNA within the nucleus is critical to ensure normal downstream nuclear functions. CTCF and cohesin act as major architectural proteins, working in concert to generate thousands of high-intensity chromatin loops. Due to their central role in loop formation, a massive research effort has been dedicated to investigating the mechanism by which CTCF and cohesin create these loops. Recent results lead to questioning the direct impact of CTCF loops on gene expression. Additionally, results of controlled depletion experiments in cell lines has indicated that genome architecture may be somewhat resistant to incomplete deficiencies in CTCF or cohesin. However, heterozygous human genetic deficiencies in CTCF and cohesin have illustrated the importance of their dosage in genome architecture, cellular processes, animal behavior, and disease phenotypes. Thus, the importance of considering CTCF or cohesin levels is especially made clear by these heterozygous germline variants that characterize genetic syndromes, which are increasingly recognized in clinical practice. Defined primarily by developmental delay and intellectual disability, the phenotypes of CTCF and cohesin deficiency illustrate the importance of architectural proteins particularly in neurodevelopment. We discuss the distinct roles of CTCF and cohesin in forming chromatin loops, highlight the major role that dosage of each protein plays in the amplitude of observed effects on gene expression, and contrast these results to heterozygous mutation phenotypes in murine models and clinical patients. Insights highlighted by this comparison have implications for future research into these newly emerging genetic syndromes.
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DOI：
10.1126/science.aar7831
发表时间：
2018-04-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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影响因子：
14.9
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影响因子：
1.5
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影响因子：
29.4
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De Giorgio R
DOI：
10.1084/jem.20161517
发表时间：
2017-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Yamashita T