Jingping Yang1,2, Difei Zhang2, Masaru Motojima3, Tsutomu Kume4, Qing Hou2, Yu Pan2, Aiping Duan2, Mingchao Zhang2, Song Jiang2, Jinhua Hou2, Jingsong Shi2, Zhaohui Qin5, Zhihong Liu1,2. 1. Medical School of Nanjing University, Nanjing, China jpyang@nju.edu.cn liuzhihong@nju.edu.cn. 2. National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. 3. Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Japan. 4. Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 5. Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia.
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.
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.
Authors: Jonathan Lefebvre; Michael Clarkson; Filippo Massa; Stephen T Bradford; Aurelie Charlet; Fabian Buske; Sandra Lacas-Gervais; Herbert Schulz; Charlotte Gimpel; Yutaka Hata; Franz Schaefer; Andreas Schedl Journal: Kidney Int Date: 2015-05-20 Impact factor: 10.612
Authors: Detlev Arendt; Jacob M Musser; Clare V H Baker; Aviv Bergman; Connie Cepko; Douglas H Erwin; Mihaela Pavlicev; Gerhard Schlosser; Stefanie Widder; Manfred D Laubichler; Günter P Wagner Journal: Nat Rev Genet Date: 2016-11-07 Impact factor: 53.242
Authors: Martin Kann; Sandrine Ettou; Youngsook L Jung; Maximilian O Lenz; Mary E Taglienti; Peter J Park; Bernhard Schermer; Thomas Benzing; Jordan A Kreidberg Journal: J Am Soc Nephrol Date: 2015-01-30 Impact factor: 10.121
Authors: Melanie Boerries; Florian Grahammer; Sven Eiselein; Moritz Buck; Charlotte Meyer; Markus Goedel; Wibke Bechtel; Stefan Zschiedrich; Dietmar Pfeifer; Denis Laloë; Christelle Arrondel; Sara Gonçalves; Marcus Krüger; Scott J Harvey; Hauke Busch; Joern Dengjel; Tobias B Huber Journal: Kidney Int Date: 2013-01-30 Impact factor: 10.612
Authors: Gemma Bullich; Andrea Domingo-Gallego; Iván Vargas; Patricia Ruiz; Laura Lorente-Grandoso; Mónica Furlano; Gloria Fraga; Álvaro Madrid; Gema Ariceta; Mar Borregán; Juan Alberto Piñero-Fernández; Lidia Rodríguez-Peña; Maria Juliana Ballesta-Martínez; Isabel Llano-Rivas; Mireia Aguirre Meñica; José Ballarín; David Torrents; Roser Torra; Elisabet Ars Journal: Kidney Int Date: 2018-05-22 Impact factor: 10.612
Authors: Fidel Ramírez; Devon P Ryan; Björn Grüning; Vivek Bhardwaj; Fabian Kilpert; Andreas S Richter; Steffen Heyne; Friederike Dündar; Thomas Manke Journal: Nucleic Acids Res Date: 2016-04-13 Impact factor: 16.971