DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation
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DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation. / Wanner, Nicola; Vornweg, Julia; Combes, Alexander; Wilson, Sean; Plappert, Julia; Rafflenbeul, Gesa; Puelles, Victor G; Rahman, Raza-Ur; Liwinski, Timur; Lindner, Saskia; Grahammer, Florian; Kretz, Oliver; Wlodek, Mary E; Romano, Tania; Moritz, Karen M; Boerries, Melanie; Busch, Hauke; Bonn, Stefan; Little, Melissa H; Bechtel-Walz, Wibke; Huber, Tobias B.
in: J AM SOC NEPHROL, Jahrgang 30, Nr. 1, 01.2019, S. 63-78.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation
AU - Wanner, Nicola
AU - Vornweg, Julia
AU - Combes, Alexander
AU - Wilson, Sean
AU - Plappert, Julia
AU - Rafflenbeul, Gesa
AU - Puelles, Victor G
AU - Rahman, Raza-Ur
AU - Liwinski, Timur
AU - Lindner, Saskia
AU - Grahammer, Florian
AU - Kretz, Oliver
AU - Wlodek, Mary E
AU - Romano, Tania
AU - Moritz, Karen M
AU - Boerries, Melanie
AU - Busch, Hauke
AU - Bonn, Stefan
AU - Little, Melissa H
AU - Bechtel-Walz, Wibke
AU - Huber, Tobias B
N1 - Copyright © 2019 by the American Society of Nephrology.
PY - 2019/1
Y1 - 2019/1
N2 - BACKGROUND: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear.METHODS: We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development.RESULTS: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression.CONCLUSIONS: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.
AB - BACKGROUND: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear.METHODS: We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development.RESULTS: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression.CONCLUSIONS: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.
KW - Journal Article
U2 - 10.1681/ASN.2018070736
DO - 10.1681/ASN.2018070736
M3 - SCORING: Journal article
C2 - 30518531
VL - 30
SP - 63
EP - 78
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 1
ER -
