Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis.
Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis.
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DOI：
10.1093/nar/gkad468
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发表时间：
2023-07-21
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
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作者：
哺乳动物红系发育可分为三个阶段：造血干/祖细胞(HSPC)、红系祖细胞(Ery-Pro)和红系前体细胞(Ery-Pre)。然而，3D基因组改变以建立阶段特定的转录程序的机制仍不清楚，这些程序对红细胞生成至关重要。在这里，我们分析了来自原代人类红系培养的特定人群在多个水平上的染色质景观。虽然区段和拓扑相关结构域在很大程度上保持不变，但H3K27Ac标记的增强子中有50%在∼与ERY-PRE中是动态的。增强子-启动子环的增强子锚定富含各自阶段特异的转录因子(TF)，表明这些转录因子协调增强子连接体重连。红细胞生成的主因子GATA1在Ery-Pro阶段占据了大部分红系基因启动子，并通过在Ery-Pre的远端区域获得结合来介导明显的局部重连，促进了红系的高效转录输出。敲除GATA1结合位点准确地取消了局部重新连接和相应的基因表达。有趣的是，击倒GATA1可以瞬时将细胞状态恢复到早期阶段，并延长祖细胞状态的窗口。这项研究通过整合多维染色质景观分析与转录输出和细胞状态相关联，揭示了发育过程中染色质重排的机制。
Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer–promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states.
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影响因子：
64.5
作者：
Dekker J;Mirny L
通讯作者：
Mirny L
影响因子：
16
作者：
Fujiwara T;O'Geen H;Keles S;Blahnik K;Linnemann AK;Kang YA;Choi K;Farnham PJ;Bresnick EH
通讯作者：
Bresnick EH
影响因子：
64.5
作者：
Deng W;Lee J;Wang H;Miller J;Reik A;Gregory PD;Dean A;Blobel GA
通讯作者：
Blobel GA
影响因子：
64.5
作者：
Hainer, Sarah J.;Boskovic, Ana;Fazzio, Thomas G.
通讯作者：
Fazzio, Thomas G.
DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
通讯作者：
Cohen D