RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation
Danya J Martell1,2,3,4, Hope E Merens1, Claudia Fiorini2,3,4
1Harvard University, Department of Genetics, Boston, MA.
Medrxiv : the Preprint Server for Health Sciences
|March 22, 2023
Summary
Disrupting RNA polymerase II pausing delays erythropoiesis by affecting cell cycle and gene expression. This reveals a role for RNA polymerase II pausing in coordinating cell cycle and differentiation.
Area of Science:
- Molecular Biology
- Gene Regulation
- Hematopoiesis
Background:
- Controlled release of paused RNA polymerase II (Pol II) into productive elongation is critical for gene regulation.
- Functional analysis of Pol II pausing is challenging due to the essential nature of regulatory factors.
Approach:
- Identified heterozygous loss-of-function mutations in SUPT5H (encoding SPT5) in beta-thalassemia patients.
- Recapitulated pathogenic mutations via SUPT5H editing in human cells.
- Analyzed Pol II pause release, gene expression, and cell cycle kinetics during erythropoiesis.
Key Points:
- Cell cycle genes are highly paused during the progenitor-to-precursor transition in erythropoiesis.
- SUPT5H mutations globally disrupted Pol II pause release, delaying this transition.
- Erythroid-specific gene expression and cell cycle kinetics showed a transient lag.
Conclusions:
- Hindering Pol II pause release perturbs proliferation and differentiation dynamics during erythropoiesis.
- Pol II pausing plays a crucial role in the temporal coordination between cell cycle and differentiation.
- This study reveals a novel mechanism linking gene regulation to developmental timing.
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