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

Publication date: 21 February 2017
Source:Cell Reports, Volume 18, Issue 8
Author(s): 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
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.

Graphical abstract

Teaser

By analyzing the transcriptome and methylome of Sirt1-null (Sirt1^−/−) murine embryonic stem cells (ESCs), Heo et al. show that Sirt1 protects against excessive DNA methylation in a subset of imprinted and germline development genes through antagonizing Dnmt3l transcription and protein stability, thereby preserving proper developmental potency of ESCs.


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