دورية أكاديمية
The transcriptional elongation factor CTR9 demarcates PRC2-mediated H3K27me3 domains by altering PRC2 subtype equilibrium.
العنوان: | The transcriptional elongation factor CTR9 demarcates PRC2-mediated H3K27me3 domains by altering PRC2 subtype equilibrium. |
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المؤلفون: | Chan NT; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA., Huang J; School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA., Ma G; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA., Zeng H; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA., Donahue K; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA., Wang Y; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA., Li L; School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Xu W; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.; UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA. |
المصدر: | Nucleic acids research [Nucleic Acids Res] 2022 Feb 28; Vol. 50 (4), pp. 1969-1992. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 1992- : Oxford : Oxford University Press Original Publication: London, Information Retrieval ltd. |
مواضيع طبية MeSH: | Breast Neoplasms*/genetics , Histones*/genetics , Histones*/metabolism , Phosphoproteins*/genetics , Transcription Factors*/genetics , Transcription Factors*/metabolism, Cell Line, Tumor ; Chromatin ; Craniofacial Abnormalities ; Female ; Humans ; Polycomb Repressive Complex 2/metabolism |
مستخلص: | CTR9 is the scaffold subunit in polymerase-associated factor complex (PAFc), a multifunctional complex employed in multiple steps of RNA Polymerase II (RNAPII)-mediated transcription. CTR9/PAFc is well known as an evolutionarily conserved elongation factor that regulates gene activation via coupling with histone modifications enzymes. However, little is known about its function to restrain repressive histone markers. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the H3K27me3 levels are strictly controlled by CTR9. Quantitative profiling of histone modifications revealed a striking increase of H3K27me3 levels upon loss of CTR9. Moreover, loss of CTR9 leads to genome-wide expansion of H3K27me3, as well as increased recruitment of PRC2 on chromatin, which can be reversed by CTR9 restoration. Further, CTR9 depletion triggers a PRC2 subtype switch from the less active PRC2.2, to the more active PRC2.1 with higher methyltransferase activity. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution provide a unique mechanism that explains the transition from transcriptionally active chromatin states to repressive chromatin states and sheds light on the biological functions of CTR9 in development and cancer. (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.) |
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معلومات مُعتمدة: | R01 CA268183 United States CA NCI NIH HHS; R01 CA236356 United States CA NCI NIH HHS; R01 CA213293 United States CA NCI NIH HHS; P30 CA014520 United States CA NCI NIH HHS; U01 CA231081 United States CA NCI NIH HHS; S10 RR029531 United States RR NCRR NIH HHS; P41 GM108538 United States GM NIGMS NIH HHS; R01 DK071801 United States DK NIDDK NIH HHS; T32 CA009135 United States CA NCI NIH HHS |
سلسلة جزيئية: | Dryad 10.5061/dryad.r7sqv9sd7 |
المشرفين على المادة: | 0 (CTR9 protein, human) 0 (Chromatin) 0 (Histones) 0 (Phosphoproteins) 0 (Transcription Factors) EC 2.1.1.43 (Polycomb Repressive Complex 2) |
SCR Disease Name: | Preauricular Fistulae, Congenital |
تواريخ الأحداث: | Date Created: 20220209 Date Completed: 20220415 Latest Revision: 20230126 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC8887485 |
DOI: | 10.1093/nar/gkac047 |
PMID: | 35137163 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1362-4962 |
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DOI: | 10.1093/nar/gkac047 |