Dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm

Zeyang Wang, Rui Fan, Angela Russo, Filippo M. Cernilogar, Alexander Nuber, Silvia Schirge, Irina Shcherbakova, Iva Dzhilyanova, Enes Ugur, Tobias Anton, Lisa Richter, Heinrich Leonhardt, Heiko Lickert and Gunnar Schotta ()
Additional contact information
Zeyang Wang: Biomedical Center, Faculty of Medicine, LMU Munich
Rui Fan: Biomedical Center, Faculty of Medicine, LMU Munich
Angela Russo: Biomedical Center, Faculty of Medicine, LMU Munich
Filippo M. Cernilogar: Biomedical Center, Faculty of Medicine, LMU Munich
Alexander Nuber: Biomedical Center, Faculty of Medicine, LMU Munich
Silvia Schirge: Institute of Stem Cell Research
Irina Shcherbakova: Biomedical Center, Faculty of Medicine, LMU Munich
Iva Dzhilyanova: Biomedical Center, Faculty of Medicine, LMU Munich
Enes Ugur: Biozentrum, LMU Munich
Tobias Anton: Biozentrum, LMU Munich
Lisa Richter: Core Facility Flow Cytometry, Faculty of Medicine, LMU Munich
Heinrich Leonhardt: Biozentrum, LMU Munich
Heiko Lickert: Institute of Stem Cell Research
Gunnar Schotta: Biomedical Center, Faculty of Medicine, LMU Munich

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Silencing of endogenous retroviruses (ERVs) is largely mediated by repressive chromatin modifications H3K9me3 and DNA methylation. On ERVs, these modifications are mainly deposited by the histone methyltransferase Setdb1 and by the maintenance DNA methyltransferase Dnmt1. Knock-out of either Setdb1 or Dnmt1 leads to ERV de-repression in various cell types. However, it is currently not known if H3K9me3 and DNA methylation depend on each other for ERV silencing. Here we show that conditional knock-out of Setdb1 in mouse embryonic endoderm results in ERV de-repression in visceral endoderm (VE) descendants and does not occur in definitive endoderm (DE). Deletion of Setdb1 in VE progenitors results in loss of H3K9me3 and reduced DNA methylation of Intracisternal A-particle (IAP) elements, consistent with up-regulation of this ERV family. In DE, loss of Setdb1 does not affect H3K9me3 nor DNA methylation, suggesting Setdb1-independent pathways for maintaining these modifications. Importantly, Dnmt1 knock-out results in IAP de-repression in both visceral and definitive endoderm cells, while H3K9me3 is unaltered. Thus, our data suggest a dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm cells. Our findings suggest that Setdb1-meditated H3K9me3 is not sufficient for IAP silencing, but rather critical for maintaining high DNA methylation.

Date: 2022
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DOI: 10.1038/s41467-022-32978-7

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