CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart.
CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart.
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DOI：
10.1101/gad.349154.121
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发表时间：
2022-04-01
影响因子：
10.5
通讯作者：
Conlon, Frank L.
中科院分区：
文献类型：
--
作者：
Robbe, Zachary L.;Shi, Wei;Wasson, Lauren K.;Scialdone, Angel P.;Wilczewski, Caralynn M.;Sheng, Xinlei;Hepperla, Austin J.;Akerberg, Brynn N.;Pu, William T.;Cristea, Ileana M.;Davis, Ian J.;Conlon, Frank L.
在这项研究中，Robbe等人研究了CHD4/NuRD如何定位于特定的心脏靶基因，因为CHD4和NuRD都不能直接结合DNA。他们将基于生物信息学的方法与质谱分析相结合，证明了CHD4在胚胎心脏发育过程中与核心心脏转录因子GATA4、NKX2-5和TBX5相互作用，从而为CHD4蛋白突变如何导致心脏特异性疾病状态提供了新的见解。核小体重塑和去乙酰化酶（NuRD）复合体是介导基因抑制的中心染色质重塑复合体之一。NuRD对包括心脏发育在内的许多发育事件至关重要。临床和遗传学研究已经为NuRD的催化成分染色体结构域解旋酶dna结合蛋白4 （CHD4）在先天性心脏病（CHD）中的作用提供了直接证据，包括心房和室间隔缺陷。此外，已经证明CHD4对哺乳动物心肌细胞的形成和功能至关重要。一个关键的未解决的问题是CHD4/NuRD如何定位于特定的心脏靶基因，因为CHD4和NuRD都不能直接结合DNA。在这里，我们将基于生物信息学的方法与质谱分析相结合，证明CHD4在胚胎心脏发育过程中与核心心脏转录因子GATA4、NKX2-5和TBX5相互作用。利用转录组学和全基因组占用数据，我们表征了GATA4、NKX2-5和TBX5抑制的基因组图谱，并确定了GATA4 - chd4、NKX2-5 - chd4和TBX5- chd4复合物的直接心脏基因靶点。这些数据被用来鉴定由这些复合物控制的假定的顺式调控元件。我们在体内对其中两种沉默基因进行了基因研究：Acta1和Myh11。我们发现，在胚胎心脏中，这些沉默子的缺失分别导致不适当的骨骼和平滑肌基因错误表达。这些结果描述了CHD4/NuRD如何定位于特定的心脏位点，并阐明了广泛表达的CHD4蛋白的突变如何导致心脏特异性疾病状态。
In this study, Robbe et al. investigated how CHD4/NuRD is localized to specific cardiac target genes, as neither CHD4 nor NuRD can directly bind DNA. They coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5, and TBX5 during embryonic heart development, thus providing new insights into how mutations in the CHD4 protein lead to cardiac-specific disease states. The nucleosome remodeling and deacetylase (NuRD) complex is one of the central chromatin remodeling complexes that mediates gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects. Furthermore, it has been demonstrated that CHD4 is essential for mammalian cardiomyocyte formation and function. A key unresolved question is how CHD4/NuRD is localized to specific cardiac target genes, as neither CHD4 nor NuRD can directly bind DNA. Here, we coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5, and TBX5 during embryonic heart development. Using transcriptomics and genome-wide occupancy data, we characterized the genomic landscape of GATA4, NKX2-5, and TBX5 repression and defined the direct cardiac gene targets of the GATA4–CHD4, NKX2-5–CHD4, and TBX5-CHD4 complexes. These data were used to identify putative cis-regulatory elements controlled by these complexes. We genetically interrogated two of these silencers in vivo: Acta1 and Myh11. We show that deletion of these silencers leads to inappropriate skeletal and smooth muscle gene misexpression, respectively, in the embryonic heart. These results delineate how CHD4/NuRD is localized to specific cardiac loci and explicates how mutations in the broadly expressed CHD4 protein lead to cardiac-specific disease states.
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DOI：
10.1093/bioinformatics/btx346
发表时间：
2017-10-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Serra E
通讯作者：
Serra E
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
11.4
作者：
Durocher, D;Charron, F;Nemer, M
通讯作者：
Nemer, M
影响因子：
2
作者：
Baban, Anwar;Pitto, Letizia;Albanese, Sonia
通讯作者：
Albanese, Sonia
影响因子：
9.8
作者：
Federspiel, Joel D.;Tandon, Panna;Conlon, Frank L.
通讯作者：
Conlon, Frank L.