Biomaterial Database

RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation. 2023

Danya J Martell, and Hope E Merens, and Claudia Fiorini, and Alexis Caulier, and Jacob C Ulirsch, and Robert Ietswaart, and Karine Choquet, and Giovanna Graziadei, and Valentina Brancaleoni, and Maria Domenica Cappellini, and Caroline Scott, and Nigel Roberts, and Melanie Proven, and Noémi Ba Roy, and Christian Babbs, and Douglas R Higgs, and Vijay G Sankaran, and L Stirling Churchman

Harvard University, Department of Genetics, Boston, MA.

The controlled release of promoter-proximal paused RNA polymerase II (Pol II) into productive elongation is a major step in gene regulation. However, functional analysis of Pol II pausing is difficult because factors that regulate pause release are almost all essential. In this study, we identified heterozygous loss-of-function mutations in SUPT5H , which encodes SPT5, in individuals with β-thalassemia unlinked to HBB mutations. During erythropoiesis in healthy human cells, cell cycle genes were highly paused at the transition from progenitors to precursors. When the pathogenic mutations were recapitulated by SUPT5H editing, Pol II pause release was globally disrupted, and the transition from progenitors to precursors was delayed, marked 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, revealing a role for Pol II pausing in the temporal coordination between the cell cycle and differentiation.