Novel enhancers conferring compensatory transcriptional regulation of Nkx2-5 in heart development

作者：Zhang, Jiejie; Li, Chen C.; Li, Xin; Liu, Yaxi; Wang, Qianhao; Zhang, Guangyu; Xiong, Haiqing; He, Aibin^*; Ai, Shanshan^*

来源：iScience, 2023, 26(4): 106509.

DOI：10.1016/j.isci.2023.106509

• SUPER-ENHANCERS
• CELL IDENTITY
• GENE
• INSIGHTS
• ELEMENTS
• NETWORKS
• BINDING
• EXPRESSION
• EVOLUTION
• DEFECTS

Cell type-specific expression of the developmental gene is conferred by distinct enhancer elements. Current knowledge about mechanisms in Nkx2-5 transcriptional regulation and its specific roles in multistage heart morphogenesis is limited. We comprehensively interrogate enhancers U1 and U2 in controlling Nkx2-5 transcription during heart development. Serial genomic deletions in mice reveal U1 and U2 function redundantly to confer Nkx2-5 expression at early stages, but U2 instead of U1 supports its expression at later stages. Combined deletions markedly reduce Nkx2-5 dosage as early as E7.5, despite being largely reinstated two days later, displaying heart malformations with precocious differentiation of cardiac progenitors. Cutting-edge low-input chromatin immunoprecipitation sequencing (ChIP-seq) confirmed that not only genomic NKX2-5 occupancy but also its regulated enhancer landscape is mostly disturbed in the double-deletion mouse hearts. Together, we propose a model that the temporal and partially compensatory regulatory function of two enhancers dictates a transcription factor (TF)'s dosage and specificity during development.

• 单位
  北京大学; 南方医科大学; 5