Sirt1 Regulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l

Jinbeom Heo; Jisun Lim; Seungun Lee; Jaeho Jeong; Hyunsook Kang; YongHwan Kim; Jeong Wook Kang; Hwan Yeul Yu; Eui Man Jeong; Kyunggon Kim; Magda Kucia; Sabine J. Waigel; Wolfgang Zacharias; Yinlu Chen; In-Gyu Kim; Mariusz Z. Ratajczak; Dong-Myung Shin

doi:10.1016/j.celrep.2017.01.074

Cell Reports (Feb 2017)

Sirt1 Regulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l

Jinbeom Heo,
Jisun Lim,
Seungun Lee,
Jaeho Jeong,
Hyunsook Kang,
YongHwan Kim,
Jeong Wook Kang,
Hwan Yeul Yu,
Eui Man Jeong,
Kyunggon Kim,
Magda Kucia,
Sabine J. Waigel,
Wolfgang Zacharias,
Yinlu Chen,
In-Gyu Kim,
Mariusz Z. Ratajczak,
Dong-Myung Shin

Affiliations

Jinbeom Heo: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Jisun Lim: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Seungun Lee: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Jaeho Jeong: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Hyunsook Kang: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
YongHwan Kim: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Jeong Wook Kang: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Hwan Yeul Yu: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Eui Man Jeong: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
Kyunggon Kim: Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Magda Kucia: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
Sabine J. Waigel: Department of Medicine and Department of Pharmacology and Toxicology, Genomics Facility, University of Louisville, Louisville, KY 40202, USA
Wolfgang Zacharias: Department of Medicine and Department of Pharmacology and Toxicology, Genomics Facility, University of Louisville, Louisville, KY 40202, USA
Yinlu Chen: Department of Medicine and Department of Pharmacology and Toxicology, Genomics Facility, University of Louisville, Louisville, KY 40202, USA
In-Gyu Kim: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
Mariusz Z. Ratajczak: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
Dong-Myung Shin: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea

DOI: https://doi.org/10.1016/j.celrep.2017.01.074
Journal volume & issue: Vol. 18, no. 8
pp. 1930 – 1945

Abstract

Read online

Embryonic stem cell (ESC) abnormalities in genome methylation hamper the utility of their therapeutic derivatives; however, the underlying mechanisms are unknown. Here, we show that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, Sirt1, selectively prevents abnormal DNA methylation of some developmental genes in murine ESCs by antagonizing Dnmt3l. Transcriptome and DNA methylome analyses demonstrated that Sirt1-null (Sirt1−/−) ESCs repress expression of a subset of imprinted and germline genes concomitant with increased DNA methylation of regulatory elements. Dnmt3l was highly expressed in Sirt1−/− ESCs, and knockdown partially rescued abnormal DNA methylation of the Sirt1 target genes. The Sirt1 protein suppressed transcription of Dnmt3l and physically interacted with the Dnmt3l protein, deacetylating and destabilizing Dnmt3l protein. Sirt1 deficiency delayed neurogenesis and spermatogenesis. These differentiation delays were significantly or partially abolished by reintroduction of Sirt1 cDNA or Dnmt3l knockdown. This study sheds light on mechanisms that restrain DNA methylation of developmentally vital genes operating in ESCs.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords