RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Internet publication |
| Language: | English |
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Cold Spring Harbor Laboratory
2023
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| _version_ | 1797112010896310272 |
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| author | Martell, DJ Merens, HE Fiorini, C Caulier, A Ulirsch, JC Ietswaart, R Choquet, K Graziadei, G Brancaleoni, V Cappellini, MD Scott, C Roberts, N Proven, M Roy, NB Babbs, C Higgs, DR Sankaran, VG Churchman, LS |
| author_facet | Martell, DJ Merens, HE Fiorini, C Caulier, A Ulirsch, JC Ietswaart, R Choquet, K Graziadei, G Brancaleoni, V Cappellini, MD Scott, C Roberts, N Proven, M Roy, NB Babbs, C Higgs, DR Sankaran, VG Churchman, LS |
| author_sort | Martell, DJ |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T08:18:24Z |
| format | Internet publication |
| id | oxford-uuid:3c184318-c013-4e05-9f55-9990fe1ce106 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:18:24Z |
| publishDate | 2023 |
| publisher | Cold Spring Harbor Laboratory |
| record_format | dspace |
| spelling | oxford-uuid:3c184318-c013-4e05-9f55-9990fe1ce1062024-01-19T08:36:01ZRNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiationInternet publicationhttp://purl.org/coar/resource_type/c_7ad9uuid:3c184318-c013-4e05-9f55-9990fe1ce106EnglishSymplectic ElementsCold Spring Harbor Laboratory2023Martell, DJMerens, HEFiorini, CCaulier, AUlirsch, JCIetswaart, RChoquet, KGraziadei, GBrancaleoni, VCappellini, MDScott, CRoberts, NProven, MRoy, NBBabbs, CHiggs, DRSankaran, VGChurchman, LSThe 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. |
| spellingShingle | Martell, DJ Merens, HE Fiorini, C Caulier, A Ulirsch, JC Ietswaart, R Choquet, K Graziadei, G Brancaleoni, V Cappellini, MD Scott, C Roberts, N Proven, M Roy, NB Babbs, C Higgs, DR Sankaran, VG Churchman, LS RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation |
| title | RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation |
| title_full | RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation |
| title_fullStr | RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation |
| title_full_unstemmed | RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation |
| title_short | RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation |
| title_sort | rna polymerase ii pausing temporally coordinates cell cycle progression and erythroid differentiation |
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