染色质域蛋白 CHD7 的一项单倍体缺失是导致 CHARGE 综合征大多数病例的基础，这是一种多系统的先天性缺陷，包括先天性心脏畸形。报道了 CHD7 在各种干细胞、祖细胞和分化细胞系中的特定上下文作用。我们以心脏喉部中胚层 (CPM) 缺失 Chd7 时出现严重缺陷为前提，研究了 CPM 中基因表达的改变，并确定了在受影响结构的形态发生中具有已知作用的特定 CHD7 结合靶基因。我们在 CPM 中产生 Chd7 的条件性敲出并使用转录组学和表观基因组学分析、活体表达分析以及与现有数据集进行生物信息学比较来分析心脏祖细胞。我们发现 CHD7 在许多涉及心脏发育的关键基因的正确表达中是必需的，尤其是在第二心脏场 (SHF) 内。我们在心脏祖细胞中鉴定到 CHD7 的结合位点，并发现在 mESC 分化期间的中胚层向心脏祖细胞转化过程中与高度动态调节的增强子相关的组蛋白标记强烈相关。此外，CHD7 与 ISL1 相互作用，共享其一部分靶点位点，并调制 SHF 祖细胞与分化的心肌细胞之间 Fgf10 表达的一个增强子。我们展示了 CHD7 通过在大多数靶基因远离的增强子上结合输配子基因网络先驱转录因子 ISL1 来调节关键心肌发生基因。CHD7 是 CHARGE 综合征中单倍体缺失的染色质重塑剂，在自闭症谱系障碍和各种癌症中有牵连。该综合征中的心脏缺陷通过神经嵴和心脏喉部中胚层的小鼠失活得到重现。CHD7 通过主要结合到远离靶基因的增强子位点，与先驱转录因子 ISL1 分享这些位点，调节心肌发生中必需的基因。 CHD7 结合的增强元件表现出非常动态的组蛋白修饰切换，这是从中胚层向心脏祖细胞的转化过程中的特征。因此，CHD7 活性的调节可能有助于直接分化不同的心血管祖细胞，以用于再生/修复治疗。

Haploinsufficiency of the chromo-domain protein CHD7 underlies most cases of CHARGE syndrome, a multisystem birth defect including congenital heart malformation. Context specific roles for CHD7 in various stem, progenitor and differentiated cell lineages have been reported. Previously we showed severe defects when Chd7 is absent from cardiopharyngeal mesoderm (CPM). Here we investigate altered gene expression in the CPM and identify specific CHD7-bound target genes with known roles in the morphogenesis of affected structures.We generated conditional KO of Chd7 in CPM and analysed cardiac progenitor cells using transcriptomic and epigenomic analyses, in vivo expression analysis, and bioinformatic comparisons with existing datasets. We show CHD7 is required for correct expression of several genes established as major players in cardiac development, especially within the second heart field (SHF). We identified CHD7 binding sites in cardiac progenitor cells and found strong association with histone marks suggestive of dynamically regulated enhancers during the mesodermal to cardiac progenitor transition of mESC differentiation. Moreover, CHD7 shares a subset of its target sites with ISL1, a pioneer transcription factor in the cardiogenic gene regulatory network, including one enhancer modulating Fgf10 expression in SHF progenitor cells versus differentiating cardiomyocytes.We show that CHD7 interacts with ISL1, binds ISL1-regulated cardiac enhancers and modulates gene expression across the mesodermal heart fields during cardiac morphogenesis.CHD7 is a chromatin remodeller haploinsufficient in CHARGE syndrome and implicated in autism spectrum disorder and various cancers. Heart defects in the syndrome are recapitulated by murine loss-of-function in two linages, neural crest and cardiopharyngeal mesoderm (CPM). CHD7 regulates vital cardiogenic genes via binding predominantly to enhancers distant from the target gene at sites often shared with the pioneer transcription factor ISL1. CHD7 bound enhancer elements show highly dynamic switching of histone modifications during the mesodermal to cardiac progenitor cell transition. Thus, manipulation of CHD7 activity may assist in directed differentiation of distinct cardiovascular progenitors for use in regenerative/repair therapeutics.© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.