Super-Enhancer-Associated Transcription Factors Maintain Transcriptional Regulation in Mature Podocytes

Significance Statement Cell fate is determined by unique transcriptional programs at different life stages. The podocyte is a critical cell type for renal function. Transcription factors like FOXC1/2 have been reported to be indispensable for podocyte maintenance, but their roles in transcription and the genome-wide regulatory network have been rarely studied. Here, FOXC1/2 are discovered to play meaningful roles in core regulatory circuits as they associate with superenhancers in glomeruli. The integration of transcriptome and cistrome analysis dissected the regulatory mechanism of FOXC1/2 to reinforce the differentiation of mature podocytes. The results reveal podocytes use an intrinsic transcriptional regulation to maintain cell identity. The study also provides a glomerulus-specific, chromatin-feature resource for further understanding podocytopathy. Background Transcriptional programs control cell fate, and identifying their components is critical for understanding diseases caused by cell lesion, such as podocytopathy. Although many transcription factors (TFs) are necessary for cell-state maintenance in glomeruli, their roles in transcriptional regulation are not well understood. Methods The distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and transcriptomics were performed to elucidate the regulatory roles of the TFs. Transgenic animal models of disease were further investigated to confirm the roles of specific TFs in podocyte maintenance. Results Superenhancer distribution revealed a group of potential TFs in core regulatory circuits in human glomerulus cells, including FOXC1/2, WT1, and LMX1B. Integration of transcriptome and cistrome data of FOXC1/2 in mice resolved transcriptional regulation in podocyte maintenance. FOXC1/2 regulated differentiation-associated transcription in mature podocytes. In both humans and animal models, mature podocyte injury was accompanied by deregulation of FOXC1/2 expression, and FOXC1/2 overexpression could protect podocytes in zebrafish. Conclusions FOXC1/2 maintain podocyte differentiation through transcriptional stabilization. The genome-wide chromatin resources support further investigation of TFs’ regulatory roles in glomeruli transcription programs.