Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD-linked transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways--including lineage decisions and genes associated with cardiomyocyte function and CHD genetics--in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.

中文翻译：

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对人TBX5单倍功能不足进行建模可预测先天性心脏病的调节网络

转录调节子的单倍不足会导致人类先天性心脏病（CHD）。然而，潜在的冠心病基因调节网络（GRN）失衡是未知的。在这里，我们定义了从人类诱导的多能干细胞（iPSC）分化为心肌细胞期间，降低了CHD连锁转录因子TBX5剂量的转录后果。我们发现了TBX5依赖性途径的高度敏感失调-包括谱系决策以及与心肌细胞功能和CHD遗传相关的基因-在离散的心肌亚群中。GRN分析确定了富含CHD基因的易感结节，表明心脏网络稳定性对TBX5剂量敏感。在小鼠中验证了GRN预测的Tbx5与Mef2c之间的遗传相互作用，表现为室间隔缺损。这些结果证明了iPSC衍生的心肌细胞异质子集中不同转录应答对TBX5剂量的敏感性。这预测了人类冠心病的候选GRN，对疾病中的定量转录调控具有影响。