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CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses
M. Vukic, J. Chouaref, V. Della Chiara, S. Dogan, F. Ratner, JZM. Hogenboom, TA. Epp, K. Chawengsaksophak, KKD. Vonk, C. Breukel, Y. Ariyurek, D. San Leon Granado, SL. Kloet, L. Daxinger
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Directory of Open Access Journals
od 2015
Freely Accessible Science Journals
od 2015
PubMed Central
od 2015
Europe PubMed Central
od 2015
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
PubMed
38335290
DOI
10.1126/sciadv.adk3384
Knihovny.cz E-zdroje
- MeSH
- DNA MeSH
- jaderné proteiny * metabolismus MeSH
- metylace DNA MeSH
- myši MeSH
- protein - isoformy genetika MeSH
- proteiny buněčného cyklu * metabolismus MeSH
- represorové proteiny genetika MeSH
- transkripční faktory genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting the deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that affected large gene clusters. In the brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3), and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.
CZ OPENSCREEN Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic
Department of Human Genetics Leiden University Medical Center Leiden Netherlands
Citace poskytuje Crossref.org
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