Kidney Week

Abstract: FR-PO921

DNMT1 in Six2 Progenitor Cells Is Essential for Transposable Element Silencing and Kidney Development

Session Information

• Development, Stem Cells, Regenerative Medicine - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

• Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Jihwan Park,

• Li, Szu-Yuan, Taipei Veterans General Hospital,, Taipei City, Taiwan

Szu-Yuan Li,

• Chung, Kiwung, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Kiwung Chung,

• Shrestha, Rojesh, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Rojesh Shrestha,

• Palmer, Matthew, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew Palmer,

• Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Katalin Susztak,

Background

In mammalians cytosine methylation (5mC) is erased in the embryo and reestablished during development and differentiation. De novo DNA methyltransferases such as Dnmt3a and 4b plays key role in establishing methylation, while Dnmt1, a hemimethylase copies methylation during cell division. Much attention has been placed on promoters and enhancer methylation as they play role in gene expression regulation.

Methods

We performed genome methylation analysis by reduced representation of bisulfate sequencing (RRBS) during kidney development. We examined the renal phenotype of mice with genetic deletion of Dnmts and Tets in the Six2+ population which can differentiate nephrons in mice.

Results

Differential methylation of enhancer regions was the most prominent when kidneys of newborn and adult mice were compared. Mice with conditional deletion of Dnmt3a, 3b, Tet1 and Tet2 showed no significant renal abnormalities. In contrast, Six2^Cre/Dnmt1^fl/fl mice died within 24hrs of birth and had small kidneys. Surprisingly, the greatest methylation difference in Dnmt1 knock-out mice was observed on transposable elements (TE). RNA sequencing also detected the expression endogenous retroviruses indicating the release of silencing of TE. In addition, Dnmt1 KO kidneys expressed high levels of genes that exclusively expressed in early embryos. The re-expression of ERV was not tolerated by the cells and induced the expression of endogenous RNA sensing pathways and interferon response and ultimately resulting in cell death.

Conclusion

Our results showed that Dnmt1-mediated DNA methylation is essential for kidney development by preventing the demethylation of TEs and dedifferentiation of progenitor cells.

Funding

• NIDDK Support