Genetic determinants and epigenetic effects of pioneer-factor occupancy.
Genetic determinants and epigenetic effects of pioneer-factor occupancy.
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DOI：
10.1038/s41588-017-0034-3
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发表时间：
2018-03
期刊：
影响因子：
30.8
通讯作者：
Meissner A
中科院分区：
文献类型：
--
作者：
Donaghey J;Thakurela S;Charlton J;Chen JS;Smith ZD;Gu H;Pop R;Clement K;Stamenova EK;Karnik R;Kelley DR;Gifford CA;Cacchiarelli D;Rinn JL;Gnirke A;Ziller MJ;Meissner A
转录因子是控制发育转变的基因调控网络的核心驱动力，因此更完整地了解它们如何进入、改变和维持组织特异性基因表达模式仍然是一个重要目标。为了系统地剖析能够或限制其活性的分子组分，我们研究了FOXA 2、GATA 4和OCT 4在几种细胞类型中的基因组占有率。尽管分类为先锋因子，但所有三个因子即使在超生理表达下也证明细胞类型特异性富集。然而，只有FOXA 2和GATA 4显示，在内源性和异位条件下，在替代细胞类型中占据的额外基因座的低富集采样。辅因子表达可导致在先前取样的靶位点的子集处的先锋因子结合增加。最后，我们证明，FOXA 2占用和变化，DNA可及性沉默顺式调控元件时，细胞周期停止在G1期，但随后的DNA甲基化的损失需要DNA复制。
Transcription factors are the core drivers of gene regulatory networks that control developmental transitions, therefore a more complete understanding of how they access, alter and maintain tissue-specific gene expression patterns remains an important goal. To systematically dissect molecular components that enable or constrain their activity, we investigated the genomic occupancy of FOXA2, GATA4 and OCT4 in several cell types. Despite a classification as pioneer factors, all three factors demonstrate cell type specific enrichment even under super-physiological expression. However, only FOXA2 and GATA4 display, in both endogenous and ectopic conditions, a low enrichment sampling of additional loci that are occupied in alternative cell types. Co-factor expression can lead to increased pioneer factor binding at subsets of previously sampled target sites. Finally, we demonstrate that FOXA2 occupancy and changes to DNA accessibility at silent cis-regulatory elements can occur when the cell cycle is halted in G1, but subsequent loss of DNA methylation requires DNA replication.
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