RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation.

Autor:	Martell DJ; Department of Genetics, Harvard University, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Merens HE; Department of Genetics, Harvard University, Boston, MA, USA., Caulier A; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Fiorini C; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ulirsch JC; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ietswaart R; Department of Genetics, Harvard University, Boston, MA, USA., Choquet K; Department of Genetics, Harvard University, Boston, MA, USA., Graziadei G; Department of Clinical Sciences and Community, University of Milan, IRCCS Ca'Granda Foundation Maggiore Policlinico Hospital, Milan, Italy., Brancaleoni V; Department of Clinical Sciences and Community, University of Milan, IRCCS Ca'Granda Foundation Maggiore Policlinico Hospital, Milan, Italy., Cappellini MD; Department of Clinical Sciences and Community, University of Milan, IRCCS Ca'Granda Foundation Maggiore Policlinico Hospital, Milan, Italy., Scott C; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Roberts N; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Proven M; Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Roy NBA; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre and BRC/NHS Translational Molecular Diagnostics Centre, John Radcliffe Hospital, Oxford, UK; Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Babbs C; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Higgs DR; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Sankaran VG; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: sankaran@broadinstitute.org., Churchman LS; Department of Genetics, Harvard University, Boston, MA, USA. Electronic address: churchman@genetics.med.harvard.edu.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2023 Oct 23; Vol. 58 (20), pp. 2112-2127.e4. Date of Electronic Publication: 2023 Aug 15.
DOI:	10.1016/j.devcel.2023.07.018
Abstrakt:	Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified heterozygous loss-of-function mutations in SUPT5H, which encodes SPT5, in individuals with β-thalassemia. During erythropoiesis in healthy human cells, cell cycle genes were highly paused as cells transition from progenitors to precursors. When the pathogenic mutations were recapitulated by SUPT5H editing, RNA Pol II pause release was globally disrupted, and as cells began transitioning from progenitors to precursors, differentiation was delayed, accompanied by a transient lag in erythroid-specific gene expression and cell cycle kinetics. Despite this delay, cells terminally differentiate, and cell cycle phase distributions normalize. Therefore, hindering pause release perturbs proliferation and differentiation dynamics at a key transition during erythropoiesis, identifying a role for RNA Pol II pausing in temporally coordinating the cell cycle and erythroid differentiation. Competing Interests: Declaration of interests V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma, Sana Biotechnology, and Cellarity, all unrelated to the present work. J.C.U. is an employee of Illumina, Inc., unrelated to the present work. R.I. is a founder, board member, and shareholder of Cellforma, unrelated to the present work. (Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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