Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Yang J

PROVIDER: S-EPMC8259645 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Yang Jingping J Zhang Difei D Motojima Masaru M Kume Tsutomu T Hou Qing Q Pan Yu Y Duan Aiping A Zhang Mingchao M Jiang Song S Hou Jinhua J Shi Jingsong J Qin Zhaohui Z Liu Zhihong Z

Journal of the American Society of Nephrology : JASN 20210326 6

<h4>Background</h4>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.<h4>Methods</h4>The distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and trans ...[more]

PMID: 33771836

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Project description:Neph3 (filtrin) is expressed in the glomerular podocytes where it localizes at the specialized cell adhesion structures of the foot processes called slit diaphragms which form the outermost layer of the glomerular filtration barrier. Neph3 protein shows homology and structural similarity to Neph1, Neph2 and nephrin, which all are crucial for maintaining the normal glomerular ultrafiltration function. The exact function of Neph3 in the kidney is not known but we have previously shown that the level of Neph3 mRNA is decreased in proteinuric diseases. This suggests that Neph3 may play a role in the pathogenesis of kidney damage, and emphasizes the need to analyze the regulatory mechanisms of Neph3 gene. In this study we investigated the transcriptional regulation of Neph3 gene by identifying transcription factors that control Neph3 expression.We cloned and characterized approximately 5 kb fragment upstream of the Neph3 gene. Neph3 proximal promoter near the transcription start site was found to be devoid of TATA and CAAT boxes, but to contain a highly GC-rich area. Using promoter reporter gene constructs, we localized the main activating regulatory region of Neph3 gene in its proximal promoter region from -105 to -57. Within this region, putative transcription factor binding sites for NF-kappaB and Sp1 were found by computational analysis. Mutational screening indicated that NF-kappaB and Sp1 response elements are essential for the basal transcriptional activity of the Neph3 promoter. Co-transfection studies further showed that NF-kappaB and Sp1 regulate Neph3 promoter activity. In addition, overexpression of NF-kappaB increased endogenous Neph3 gene expression. Chromatin immunoprecipitation assay using cultured human podocytes demonstrated that both NF-kappaB and Sp1 interact with the Neph3 promoter.Our results show that NF-kappaB and Sp1 are key regulators of Neph3 expression at the basal level in podocytes, therefore providing new insight into the molecular mechanisms that contribute to the expression of Neph3 gene.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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