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J Am Soc Nephrol. 2018 Dec 5. pii: ASN.2018070736. doi: 10.1681/ASN.2018070736. [Epub ahead of print]

DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation.

Author information

1
III. Department of Medicine, n.wanner@uke.de t.huber@uke.de.
2
Faculty of Medicine, Department of Medicine IV, Medical Center-University of Freiburg, and.
3
Faculty of Biology.
4
Anatomy and Neuroscience.
5
Cell Biology Theme, Murdoch Children's Research Institute, Melbourne, Australia.
6
III. Department of Medicine.
7
Institute of Medical Systems Biology, Center for Molecular Neurobiology, and.
8
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9
Department of Neuroanatomy, University of Freiburg, Freiburg, Germany.
10
Physiology, and.
11
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia.
12
Child Health Research Centre and School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia.
13
German Cancer Consortium, Heidelberg, Germany.
14
German Cancer Research Center, Heidelberg, Germany.
15
Institute of Molecular Medicine and Cell Research.
16
Lübeck Institute of Experimental Dermatology, Lübeck, Germany; and.
17
Laboratory of Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
18
Pediatrics, University of Melbourne, Melbourne, Australia.
19
Centre for Biological Signalling Studies (BIOSS) and Center for Biological Systems Analysis (ZBSA), and.
20
Freiburg Institute for Advanced Studies, Albert Ludwig University of Freiburg, Freiburg, Germany; Departments of.

Abstract

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.

KEYWORDS:

DNA methylation; Dnmt1; Dnmt3a/b; epigenetics; kidney development; nephron progenitor cells

PMID:
30518531
DOI:
10.1681/ASN.2018070736

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