RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation.
Danya J Martell1, Hope E Merens2, Alexis Caulier3
1Department 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.
Developmental Cell
|August 16, 2023
Summary
Disrupting RNA polymerase II (RNA Pol II) pausing delays cell cycle and erythroid differentiation. This study reveals RNA Pol II pausing
Area of Science:
- Molecular Biology
- Gene Regulation
- Erythropoiesis
Background:
- Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is vital for gene regulation.
- Studying RNA Pol II pausing is difficult due to the essential nature of most pause-release factors.
Purpose of the Study:
- To investigate the role of SUPT5H mutations in RNA Pol II pausing and its impact on erythropoiesis.
- To understand how disrupted RNA Pol II pause release affects cell cycle and differentiation dynamics.
Main Methods:
- Identification of heterozygous loss-of-function mutations in SUPT5H in individuals with β-thalassemia.
- Recapitulation of pathogenic mutations via SUPT5H editing in human cells.
- Analysis of RNA Pol II pausing, gene expression, cell cycle kinetics, and differentiation during erythropoiesis.
Main Results:
- SUPT5H mutations globally disrupted RNA Pol II pause release.
- Disrupted pausing caused a delay in erythroid differentiation and transient lags in erythroid gene expression and cell cycle kinetics during progenitor-to-precursor transition.
- Despite the delay, terminal differentiation and cell cycle distributions eventually normalized.
Conclusions:
- Hindering RNA Pol II pause release perturbs proliferation and differentiation dynamics during erythropoiesis.
- RNA Pol II pausing plays a critical role in the temporal coordination of cell cycle and erythroid differentiation.
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