BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease.
BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease.
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DOI：
10.1038/ncomms16034
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发表时间：
2017-07-24
影响因子：
16.6
通讯作者：
Riley PR
中科院分区：
文献类型：
--
作者：
Vieira JM;Howard S;Villa Del Campo C;Bollini S;Dubé KN;Masters M;Barnette DN;Rohling M;Sun X;Hankins LE;Gavriouchkina D;Williams R;Metzger D;Chambon P;Sauka-Spengler T;Davies B;Riley PR
心外膜衍生细胞（EPDCs）在发育过程中参与心血管细胞类型，并在成年期通过重新激活胎儿基因程序来促进新生血管和心肌形成，从而对胸腺素β4 （t - β4）和心肌梗死（MI）做出反应。心外膜基因（再）激活的机制尚不清楚。在这里，我们发现BRG1是SWI/SNF染色质重塑复合体的基本atp酶亚基，是Wilms ' tumor 1 （Wt1）的表达、胎儿EPDC激活和随后向冠状动脉平滑肌分化以及心肌梗死时恢复Wt1活性所必需的。BRG1与Tβ4物理相互作用，并被CCAAT/增强子结合蛋白β (C/EBPβ)募集到Wt1位点的离散调控元件。brg1 - t - β4的协同结合促进了Wt1作为胚胎epdc的主要调控因子的最佳转录。此外，染色质免疫沉淀测序显示BRG1在其他关键位点结合，表明SWI/SNF在胎儿心外膜基因程序中具有活性。这些发现揭示了染色质重塑在心血管发育和修复过程中激活EPDCs的基本功能。用Tβ4激活成年小鼠心脏激活休眠的心外膜源性细胞，以帮助修复受损的心肌。在这里，Vieira等人解释了这一过程，并表明Tβ4通过改变Wt1位点的表观遗传景观，结合染色质重塑者BRG1并激活Wt1， Wt1是心外膜上皮向间质转化的关键调节因子。
Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin–remodelling complex, is required for expression of Wilms’ tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tβ4 and is recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wt1 locus. BRG1-Tβ4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin–remodelling in the activation of EPDCs during cardiovascular development and repair. Priming of the adult mouse heart with Tβ4 activates dormant epicardium-derived cells to aid repair of injured myocardium. Here, Vieira et al. explain this process and show that Tβ4 binds a chromatin remodeller BRG1 and activates Wt1, the key regulator of epicardial epithelial-to-mesenchymal transformation, by altering the epigenetic landscape of the Wt1 locus.
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DOI：
10.1007/s12265-012-9377-4
发表时间：
2012-10-01
影响因子：
3.4
作者：
Schlueter, Jan;Brand, Thomas
通讯作者：
Brand, Thomas
影响因子：
11.4
作者：
Reyes, JC;Barra, J;Yaniv, M
通讯作者：
Yaniv, M
影响因子：
10.5
作者：
Ross-Innes, Caryn S.;Stark, Rory;Carroll, Jason S.
通讯作者：
Carroll, Jason S.
影响因子：
25
作者：
Madisen L;Zwingman TA;Sunkin SM;Oh SW;Zariwala HA;Gu H;Ng LL;Palmiter RD;Hawrylycz MJ;Jones AR;Lein ES;Zeng H
通讯作者：
Zeng H
影响因子：
64.5
作者：
Liu, R;Liu, H;Zhao, KJ
通讯作者：
Zhao, KJ