While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

虽然介导调控元件-启动子相互作用的拓扑关联域 (TAD) 和环中的 3D 染色质组织对于组织特异性基因调控至关重要，但它们在人类孟德尔疾病中的参与程度在很大程度上尚不清楚。在这里，我们鉴定了 7 个家族，它们呈现出与 4q25 上 2 个 CTCF 结合位点的杂合缺失相关的新心脏实体，从而诱导 TAD 融合和染色质构象重塑。 CTCF 结合位点位于距配对样同源域转录因子 2基因 ( PITX2 ) 1 Mb 处的基因荒漠中。通过在小鼠基因组中引入人类缺失的直系同源物，我们概括了患者的表型，并分别表征了窦房结（异位激活）和心室（减少）中PITX2表达的相反失调。在人类诱导多能干细胞衍生的心肌细胞中进行的染色质构象测定（含有家族#1中鉴定出的最小缺失）揭示了 TAD 的构象重塑和融合。我们得出的结论是，CTCF 结合位点缺失介导的 TAD 重塑会导致一种新的常染色体显性孟德尔心脏病。