-transparent.png){kind=logo}
RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation. 2023
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
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.
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.
Related Publications
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
April 2022,
Science advances,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
May 2018,
Proceedings of the National Academy of Sciences of the United States of America,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
March 2014,
Development (Cambridge, England),
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
November 2009,
Molecular cell,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
February 2000,
Frontiers in bioscience : a journal and virtual library,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
September 2016,
Blood,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
May 2020,
Molecular cell,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
January 2022,
Open biology,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
September 2013,
The Journal of biological chemistry,
Danya J Martell, and
Hope E Merens, and
Alexis Caulier, and
Claudia Fiorini, 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 B A Roy, and
Christian Babbs, and
Douglas R Higgs, and
Vijay G Sankaran, and
L Stirling Churchman
October 2012,
Genes & development,
