GADD45A binds R-loops and recruits TET1 to CpG island promoters
| Autor: | Emil Karaulanov, Philipp Trnka, Ingrid Grummt, Khelifa Arab, Andrea I. Schäfer, Michael U. Musheev, Christof Niehrs |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Epigenomics
Transcription Genetic DNA damage Ribonuclease H Cell Cycle Proteins Biology Article Cell Line Epigenesis Genetic Mixed Function Oxygenases Mice 03 medical and health sciences 0302 clinical medicine Transcription (biology) Proto-Oncogene Proteins Genetics Animals Humans Epigenetics Promoter Regions Genetic 030304 developmental biology Demethylation 0303 health sciences Cell Cycle Nuclear Proteins Promoter DNA Methylation Chromatin Cell biology DNA-Binding Proteins HEK293 Cells DNA demethylation CpG site CpG Islands RNA Long Noncoding 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | R-loops are DNA-RNA hybrids enriched at CpG islands (CGIs) that can regulate chromatin states1-8. How R-loops are recognized and interpreted by specific epigenetic readers is unknown. Here we show that GADD45A (growth arrest and DNA damage protein 45A) binds directly to R-loops and mediates local DNA demethylation by recruiting TET1 (ten-eleven translocation 1). Studying the tumor suppressor TCF21 (ref. 9), we find that antisense long noncoding (lncRNA) TARID (TCF21 antisense RNA inducing promoter demethylation) forms an R-loop at the TCF21 promoter. Binding of GADD45A to the R-loop triggers local DNA demethylation and TCF21 expression. TARID transcription, R-loop formation, DNA demethylation, and TCF21 expression proceed sequentially during the cell cycle. Oxidized DNA demethylation intermediates are enriched at genomic R-loops and their levels increase upon RNase H1 depletion. Genomic profiling in embryonic stem cells identifies thousands of R-loop-dependent TET1 binding sites at CGIs. We propose that GADD45A is an epigenetic R-loop reader that recruits the demethylation machinery to promoter CGIs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink