Transcriptional regulatory control of mammalian nephron progenitors revealed by multi-factor cistromic analysis and genetic studies

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  • O’Brien, Lori L.
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
  • Guo, Qiuyu
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
  • Bahrami-Samani, Emad
    • Other Affiliation: Department of Molecular and Computational Biology; University of Southern California
  • Park, Joo-Seop
    • ORCID: 0000-0002-4190-4386
    • Other Affiliation: Division of Pediatric Urology and Division of Developmental Biology; Cincinnati Children's Hospital Medical Center
  • Hasso, Sean M.
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
  • Lee, Young-Jin
    • Other Affiliation: iDream Research Center; Mizmedi Women's Hospital
  • Fang, Alan
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
  • Kim, Albert D.
    • ORCID: 0000-0002-1334-3251
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
  • Guo, Jinjin
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
  • Hong, Trudy M.
    • Other Affiliation: Department of Anatomy; Biochemistry and Physiology; University of Hawaii at Manoa
  • Peterson, Kevin A.
    • Other Affiliation: The Jackson Laboratory
  • Lozanoff, Scott
    • ORCID: 0000-0001-9089-3153
    • Other Affiliation: Department of Anatomy; Biochemistry and Physiology; University of Hawaii at Manoa
  • Raviram, Ramya
    • Other Affiliation: Ludwig Institute for Cancer Research; Department of Cellular and Molecular Medicine; Institute of Genomic Medicine; Moores Cancer Center; University of California San Diego
  • Ren, Bing
    • Other Affiliation: Ludwig Institute for Cancer Research; Department of Cellular and Molecular Medicine; Institute of Genomic Medicine; Moores Cancer Center; University of California San Diego
  • Fogelgren, Ben
    • ORCID: 0000-0001-9882-7839
    • Other Affiliation: Department of Anatomy; Biochemistry and Physiology; University of Hawaii at Manoa
  • Smith, Andrew D.
    • Other Affiliation: Department of Molecular and Computational Biology; University of Southern California
  • Valouev, Anton
    • Other Affiliation: Department of Preventative Medicine; Division of Bioinformatics; Keck School of Medicine; University of Southern California
  • McMahon, Andrew P.
    • Other Affiliation: Department of Stem Cell Biology and Regenerative Medicine; Broad-CIRM Center; Keck School of Medicine; University of Southern California
Abstract
  • Nephron progenitor number determines nephron endowment; a reduced nephron count is linked to the onset of kidney disease. Several transcriptional regulators including Six2, Wt1, Osr1, Sall1, Eya1, Pax2, and Hox11 paralogues are required for specification and/or maintenance of nephron progenitors. However, little is known about the regulatory intersection of these players. Here, we have mapped nephron progenitor-specific transcriptional networks of Six2, Hoxd11, Osr1, and Wt1. We identified 373 multi-factor associated ‘regulatory hotspots’ around genes closely associated with progenitor programs. To examine their functional significance, we deleted ‘hotspot’ enhancer elements for Six2 and Wnt4. Removal of the distal enhancer for Six2 leads to a ~40% reduction in Six2 expression. When combined with a Six2 null allele, progeny display a premature depletion of nephron progenitors. Loss of the Wnt4 enhancer led to a significant reduction of Wnt4 expression in renal vesicles and a mildly hypoplastic kidney, a phenotype also enhanced in combination with a Wnt4 null mutation. To explore the regulatory landscape that supports proper target gene expression, we performed CTCF ChIP-seq to identify insulator-boundary regions. One such putative boundary lies between the Six2 and Six3 loci. Evidence for the functional significance of this boundary was obtained by deep sequencing of the radiation-induced Brachyrrhine (Br) mutant allele. We identified an inversion of the Six2/Six3 locus around the CTCF-bound boundary, removing Six2 from its distal enhancer regulation, but placed next to Six3 enhancer elements which support ectopic Six2 expression in the lens where Six3 is normally expressed. Six3 is now predicted to fall under control of the Six2 distal enhancer. Consistent with this view, we observed ectopic Six3 in nephron progenitors. 4C-seq supports the model for Six2 distal enhancer interactions in wild-type and Br/+ mouse kidneys. Together, these data expand our view of the regulatory genome and regulatory landscape underpinning mammalian nephrogenesis.
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  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 14
Journal issue
  • 1
Page start
  • e1007181
Language
  • English
ISSN
  • 1553-7404
  • 1553-7390

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