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Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation

Kaluscha, Sebastian ; Domcke, Silvia ; Wirbelauer, Christiane ; Stadler, Michael B ; Durdu, Sevi ; Burger, Lukas ; Schübeler, Dirk

Nature genetics, 2022-12, Vol.54 (12), p.1895-1906 [Peer Reviewed Journal]

United States: Nature Publishing Group

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Title:
Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation
Author: Kaluscha, Sebastian ; Domcke, Silvia ; Wirbelauer, Christiane ; Stadler, Michael B ; Durdu, Sevi ; Burger, Lukas ; Schübeler, Dirk
Subjects: Animals ; Binding ; Cell cycle ; Cloning ; Combinatorial analysis ; CpG islands ; CRISPR ; Cytosine ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - genetics ; Embryo cells ; Epigenetics ; Gene expression ; Genes ; Genomes ; Hepatocyte Nuclear Factor 6 ; Humans ; In vivo methods and tests ; Mammals ; Mice ; Morphology ; Neurons ; Proteins ; Regulatory sequences ; Stem cell transplantation ; Stem cells ; Transcription factors ; Transcription Factors - genetics
Is Part Of: Nature genetics, 2022-12, Vol.54 (12), p.1895-1906
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: Cytosine methylation efficiently silences CpG-rich regulatory regions of genes and repeats in mammalian genomes. To what extent this entails direct inhibition of transcription factor (TF) binding versus indirect inhibition via recruitment of methyl-CpG-binding domain (MBD) proteins is unclear. Here we show that combinatorial genetic deletions of all four proteins with functional MBDs in mouse embryonic stem cells, derived neurons or a human cell line do not reactivate genes or repeats with methylated promoters. These do, however, become activated by methylation-restricted TFs if DNA methylation is removed. We identify several causal TFs in neurons, including ONECUT1, which is methylation sensitive only at a motif variant. Rampantly upregulated retrotransposons in methylation-free neurons feature a CRE motif, which activates them in the absence of DNA methylation via methylation-sensitive binding of CREB1. Our study reveals methylation-sensitive TFs in vivo and argues that direct inhibition, rather than indirect repression by the tested MBD proteins, is the prevailing mechanism of methylation-mediated repression at regulatory regions and repeats.
Publisher: United States: Nature Publishing Group
Language: English

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Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation

Kaluscha, Sebastian ; Domcke, Silvia ; Wirbelauer, Christiane ; Stadler, Michael B ; Durdu, Sevi ; Burger, Lukas ; Schübeler, Dirk

United States: Nature Publishing Group

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