title: Epigenetic States of nephron progenitors and epithelial differentiation.
abstract: In mammals, formation of new nephrons ends perinatally due to consumption of mesenchymal progenitor cells. Premature depletion of progenitors due to prematurity or postnatal loss of nephrons due to injury causes chronic kidney disease and hypertension. Intensive efforts are currently invested in designing regenerative strategies to form new nephron progenitors from pluripotent cells, which upon further differentiation provide a potential source of new nephrons. To know if reprogramed renal cells can maintain their identity and fate requires knowledge of the epigenetic states of native nephron progenitors and their progeny. In this article, we summarize current knowledge and gaps in the epigenomic landscape of the developing kidney. We now know that Pax2/PTIP/H3K4 methyltransferase activity provides the initial epigenetic specification signal to the metanephric mesenchyme. During nephrogenesis, the cap mesenchyme housing nephron progenitors is enriched in bivalent chromatin marks; as tubulogenesis proceeds, the tubular epithelium acquires H3K79me2. The latter mark is uniquely induced during epithelial differentiation. Analysis of histone landscapes in clonal metanephric mesenchyme cell lines and in Wilms tumor and normal fetal kidney has revealed that promoters of poised nephrogenesis genes carry bivalent histone signatures in progenitors. Differentiation or stimulation of Wnt signaling promotes resolution of bivalency; this does not occur in Wilms tumor cells consistent with their developmental arrest. The use of small cell number ChIP-Seq should facilitate the characterization of the chromatin landscape of the metanephric mesenchyme and various nephron compartments during nephrogenesis. Only then we will know if stem and somatic cell reprogramming into kidney progenitors recapitulates normal development.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virgina.
authors.forename: Mazhar
authors.initials: M
authors.lastname: Adli
authors.forename: Mahmut
authors.initials: M
authors.lastname: Parlak
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.forename: Samir S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D057890:Epigenomics; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology; D009399:Nephrons / Q000166:cytology* / Q000378:metabolism; D011247:Pregnancy; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051153:Wnt Proteins
keywords: CHROMATIN SIGNATURE; EPIGENETICS; KIDNEY DEVELOPMENT; NEPHROGENESIS; NEPHRON PROGENITORS