title: Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators.
abstract: Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. By contrast, Six2 maintains later progenitor self-renewal from the onset of nephrogenesis. We compared the regulatory actions of Six2 in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Furthermore, RNA-seq and immunostaining revealed overlapping SIX1 and SIX2 activity in 16 week human fetal nephron progenitors. Comparative bioinformatic analysis of human SIX1 and SIX2 ChIP-seq showed each factor targeted a similar set of cis-regulatory modules binding an identical target recognition motif. In contrast to the mouse where Six2 binds its own enhancers but does not interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. By contrast, the mouse establishes only an auto-regulatory Six2 loop. These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Lori L
authors.initials: LL
authors.lastname: O'Brien
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA Division of Bioinformatics, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: YoungJin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Benazet
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Whitney
authors.affiliation: Division of Bioinformatics, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA valouev@usc.edu amcmahon@med.usc.edu.
authors.forename: Anton
authors.initials: A
authors.lastname: Valouev
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA valouev@usc.edu amcmahon@med.usc.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D008822:Mice, Transgenic; D008954:Models, Biological; D009399:Nephrons / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C099236:SIX1 protein, human; C484762:SIX2 protein, human; C490947:Six1 protein, mouse; C497420:Six2 protein, mouse; D014157:Transcription Factors
keywords: Nephrogenesis; Nephron; Regulatory network; Six1/2; Transcription