Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis.
Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis.
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DOI：
10.1101/gr.168930.113
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发表时间：
2014-06
期刊：
影响因子：
7
通讯作者：
Pennacchio LA
中科院分区：
文献类型：
--
作者：
Attanasio C;Nord AS;Zhu Y;Blow MJ;Biddie SC;Mendenhall EM;Dixon J;Wright C;Hosseini R;Akiyama JA;Holt A;Plajzer-Frick I;Shoukry M;Afzal V;Ren B;Bernstein BE;Rubin EM;Visel A;Pennacchio LA
SMARCA 4（在人类中也称为BRG 1）染色质重塑因子对于在早期哺乳动物发育期间建立谱系特异性染色质状态至关重要。然而，SMARCA 4在胚胎发生过程中组织特异性基因调控中的作用仍然不清楚。为了研究SMARCA 4在分化组织中的全基因组结合景观，我们设计了Smarca 4FLAG敲入小鼠系。使用ChIP-seq，我们在妊娠中期（E11.5）的六个胚胎小鼠组织（前脑，后脑，神经管，心脏，肢体和面部）中鉴定了151，000个SMARCA 4相关区域。这些区域中的大多数远离启动子并显示动态占用，其中最远的SMARCA 4位点（73%）局限于单个或有限的组织子集。为了进一步表征这些区域，我们分析了相同组织中的活性和抑制性组蛋白标记，并检查了信息染色质状态和SMARCA 4结合的交叉点。这揭示了不同类别的远端SMARCA 4相关元件，其特征在于激活和抑制染色质签名，这些签名与基因表达的组织特异性上调或下调以及相关的活性/抑制生物学途径相关。我们进一步证明了SMARCA 4相关元件的预测活性调节特性的组织特异性增强子的回顾性分析和转基因小鼠试验中SMARCA 4结合区域的直接测试。我们的研究结果表明SMARCA 4在体内远端调控序列处具有双重活性/抑制功能，并支持其在胚胎发育过程中组织特异性基因调控中的作用。
The SMARCA4 (also known as BRG1 in humans) chromatin remodeling factor is critical for establishing lineage-specific chromatin states during early mammalian development. However, the role of SMARCA4 in tissue-specific gene regulation during embryogenesis remains poorly defined. To investigate the genome-wide binding landscape of SMARCA4 in differentiating tissues, we engineered a Smarca4FLAG knock-in mouse line. Using ChIP-seq, we identified ∼51,000 SMARCA4-associated regions across six embryonic mouse tissues (forebrain, hindbrain, neural tube, heart, limb, and face) at mid-gestation (E11.5). The majority of these regions was distal from promoters and showed dynamic occupancy, with most distal SMARCA4 sites (73%) confined to a single or limited subset of tissues. To further characterize these regions, we profiled active and repressive histone marks in the same tissues and examined the intersection of informative chromatin states and SMARCA4 binding. This revealed distinct classes of distal SMARCA4-associated elements characterized by activating and repressive chromatin signatures that were associated with tissue-specific up- or down-regulation of gene expression and relevant active/repressed biological pathways. We further demonstrate the predicted active regulatory properties of SMARCA4-associated elements by retrospective analysis of tissue-specific enhancers and direct testing of SMARCA4-bound regions in transgenic mouse assays. Our results indicate a dual active/repressive function of SMARCA4 at distal regulatory sequences in vivo and support its role in tissue-specific gene regulation during embryonic development.
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影响因子：
10.5
作者：
Bilodeau, Steve;Vallette-Kasic, Sophie;Drouin, Jacques
通讯作者：
Drouin, Jacques
影响因子：
9.8
作者：
Ahituv N;Zhu Y;Visel A;Holt A;Afzal V;Pennacchio LA;Rubin EM
通讯作者：
Rubin EM
影响因子：
5.3
作者：
De, Supriyo;Wurster, Andrea L.;Pazin, Michael J.
通讯作者：
Pazin, Michael J.
影响因子：
10.5
作者：
Bultman, SJ;Gebuhr, TC;Magnuson, T
通讯作者：
Magnuson, T
影响因子：
64.8
作者：
Chi, TH;Wan, M;Crabtree, GR
通讯作者：
Crabtree, GR