Sistema de Salut de Catalunya
Institut Català de la Salut
[Sansó M] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Cancer Genomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Parua PK] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [Pinto D, Pagé V] Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada. [Svensson JP] Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. [Bitton DA] Research Department of Genetics, Evolution & Environment, University College, London, UK
Vall d'Hebron Barcelona Hospital Campus
2021-11-04T13:52:42Z
2021-11-04T13:52:42Z
2020-07-27
Regulació gènica
Regulación genética
Gene Regulation
Mono-ubiquitylation of histone H2B (H2Bub1) and phosphorylation of elongation factor Spt5 by cyclin-dependent kinase 9 (Cdk9) occur during transcription by RNA polymerase II (RNAPII), and are mutually dependent in fission yeast. It remained unclear whether Cdk9 and H2Bub1 cooperate to regulate the expression of individual genes. Here, we show that Cdk9 inhibition or H2Bub1 loss induces intragenic antisense transcription of ∼10% of fission yeast genes, with each perturbation affecting largely distinct subsets; ablation of both pathways de-represses antisense transcription of over half the genome. H2Bub1 and phospho-Spt5 have similar genome-wide distributions; both modifications are enriched, and directly proportional to each other, in coding regions, and decrease abruptly around the cleavage and polyadenylation signal (CPS). Cdk9-dependence of antisense suppression at specific genes correlates with high H2Bub1 occupancy, and with promoter-proximal RNAPII pausing. Genetic interactions link Cdk9, H2Bub1 and the histone deacetylase Clr6-CII, while combined Cdk9 inhibition and H2Bub1 loss impair Clr6-CII recruitment to chromatin and lead to decreased occupancy and increased acetylation of histones within gene coding regions. These results uncover novel interactions between co-transcriptional histone modification pathways, which link regulation of RNAPII transcription elongation to suppression of aberrant initiation.
National Institutes of Health [R35GM127289 to R.P.F.]; Canadian Institutes of Health Research [MOP-130362 to J.C.T.]; Natural Sciences and Engineering Council of Canada [RGPIN 03661-15 to J.C.T.]; Wellcome Trust Senior Investigator Award [095598/Z/11/Z to J.B.]; Swedish Research Council [VR2015-02312]; Cancerfonden [CAN2016/576 awards to P.S.]; J.C.T. is supported by a fellowship from Fond de recherche Quebec Santé [33115]. Funding for open access charge: National Institutes of Health (USA); Canadian Institutes of Health Research.
Article
Published version
English
Genòmica; Quinases dependents de ciclina; Transcripció genètica - Regulació; PHENOMENA AND PROCESSES::Chemical Phenomena::Biochemical Phenomena::Transcription, Genetic::Transcription Elongation, Genetic; CHEMICALS AND DRUGS::Enzymes and Coenzymes::Enzymes::Multifunctional Enzymes::Cyclin-Dependent Kinase 9; DISCIPLINES AND OCCUPATIONS::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Genomics; FENÓMENOS Y PROCESOS::fenómenos químicos::fenómenos bioquímicos::transcripción genética::elongación de la transcripción genética; COMPUESTOS QUÍMICOS Y DROGAS::enzimas y coenzimas::enzimas::enzimas multifuncionales::cinasa 9 dependiente de la ciclina; DISCIPLINAS Y OCUPACIONES::disciplinas de las ciencias naturales::disciplinas de las ciencias biológicas::biología::biología computacional::genómica
Oxford University Press
Nucleic Acids Research;48(13)
https://doi.org/10.1093/nar/gkaa474
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
