A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape via cooperation between BAF and p63.
A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape via cooperation between BAF and p63.
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DOI：
10.1186/s13059-015-0840-9
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发表时间：
2015-12-18
期刊：
影响因子：
12.3
通讯作者：
Khavari PA
中科院分区：
文献类型：
--
作者：
Bao X;Rubin AJ;Qu K;Zhang J;Giresi PG;Chang HY;Khavari PA
开放染色质区域在发育过程中与活性调控元件相关，在疾病中失调。BAF （SWI/SNF）复合体对发育至关重要，并且已被证明在体外重塑重构的染色质，并在体内控制几个单独区域的可及性。然而，目前尚不清楚BAF在何处以及如何控制开放染色质景观来调节发育过程，如人类表皮分化。使用一种新的“板上”atac测序方法来分析具有少量贴壁细胞的开放染色质景观，我们证明BAF复合物对于维持表皮分化中11.6%的开放染色质区域至关重要。这些依赖baf的开放染色质区域具有高度的细胞类型特异性，并且富含p63（一种主表皮转录因子）的结合位点。p63结合位点的DNA序列本质上有利于核小体的形成，并且在没有p63的其他细胞类型中无法进入以防止异位激活。在表皮细胞中，BAF和p63相互招募以维持14,853个开放的染色质区域。我们进一步证明，BAF和p63共同将核小体定位在远离p63结合位点的位置，并利用转录机制来控制组织分化。在表皮分化过程中，BAF通过与主转录因子p63合作维持谱系特异性的开放染色质区域，在控制开放染色质景观方面表现出高特异性。本文的在线版本（doi:10.1186/s13059-015-0840-9）包含补充材料，仅供授权用户使用。
Open chromatin regions are correlated with active regulatory elements in development and are dysregulated in diseases. The BAF (SWI/SNF) complex is essential for development, and has been demonstrated to remodel reconstituted chromatin in vitro and to control the accessibility of a few individual regions in vivo. However, it remains unclear where and how BAF controls the open chromatin landscape to regulate developmental processes, such as human epidermal differentiation. Using a novel “on-plate” ATAC-sequencing approach for profiling open chromatin landscapes with a low number of adherent cells, we demonstrate that the BAF complex is essential for maintaining 11.6 % of open chromatin regions in epidermal differentiation. These BAF-dependent open chromatin regions are highly cell-type-specific and are strongly enriched for binding sites for p63, a master epidermal transcription factor. The DNA sequences of p63 binding sites intrinsically favor nucleosome formation and are inaccessible in other cell types without p63 to prevent ectopic activation. In epidermal cells, BAF and p63 mutually recruit each other to maintain 14,853 open chromatin regions. We further demonstrate that BAF and p63 cooperatively position nucleosomes away from p63 binding sites and recruit transcriptional machinery to control tissue differentiation. BAF displays high specificity in controlling the open chromatin landscape during epidermal differentiation by cooperating with the master transcription factor p63 to maintain lineage-specific open chromatin regions. The online version of this article (doi:10.1186/s13059-015-0840-9) contains supplementary material, which is available to authorized users.