DNMT1 in Progenitor Cells Is Essential for Transposable Element Silencing and Kidney Development.

BACKGROUND

Cytosine methylation of regulatory regions, such as promoters and enhancers, plays a key role in regulating gene expression, however, its role in kidney development has not been analyzed.

METHODS

To identify functionally important epigenome-modifying enzymes and genome regions where methylation modifications are functionally important for kidney development, we performed genome-wide methylation analysis, expression profiling, and systematic genetic targeting of DNA methyltransferases (, , and ) and Ten-eleven translocation methylcytosine hydroxylases () in nephron progenitor cells () in mice.

RESULTS

Genome-wide methylome analysis indicated dynamic changes on promoters and enhancers during development. , , and mice showed no significant structural or functional renal abnormalities. In contrast, mice died within 24 hours of birth, from a severe kidney developmental defect. Genome-wide methylation analysis indicated a marked loss of methylation of transposable elements. RNA sequencing detected endogenous retroviral transcripts. Expression of intracellular viral sensing pathways (RIG-I), early embryonic, nonrenal lineage genes and increased cell death contributed to the phenotype development. In podocytes, loss of , , , or did not lead to functional or structural differences at baseline or after toxic injury.

CONCLUSIONS

Genome-wide cytosine methylation and gene expression profiling showed that by silencing embryonic, nonrenal lineage genes and transposable elements, DNMT1-mediated cytosine methylation is essential for kidney development.