|
| Status |
Public on Sep 29, 2022 |
| Title |
Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation [ATAC-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
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 stem cells, derived neurons or a human cell line does 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 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.
|
| |
|
| Overall design |
ATAC-seq in mouse ESCs and derived neurons. WT, MBD-QKO, DNMT-TKO and DNMT-TKO with CREB1-KO (neurons only). All conditions with minimum two replicates.
|
| |
|
| Contributor(s) |
Kaluscha S, Burger L, Schubeler D, Domcke S |
| Citation(s) |
36471082 |
| |
| Submission date |
Sep 20, 2021 |
| Last update date |
Dec 15, 2022 |
| Contact name |
Dirk Schuebeler |
| Organization name |
Friedrich Miescher Institute for Biomedical Research
|
| Street address |
Maulbeerstrasse 66
|
| City |
Basel |
| ZIP/Postal code |
4058 |
| Country |
Switzerland |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (25)
|
|
| This SubSeries is part of SuperSeries: |
| GSE184470 |
Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation |
|
| Relations |
| BioProject |
PRJNA764722 |
| SRA |
SRP337934 |
Less...
More...