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The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.

Lau, C-I; Rowell, J; Yanez, DC; Solanki, A; Ross, S; Ono, M; Crompton, T; (2021) The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection. Development 10.1242/dev.199754. (In press). Green open access

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Abstract

During positive selection at the transition from CD4+CD8+ double-positive (DP) to single positive (SP) thymocyte, TCR signalling results in appropriate MHC-restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection. Foxa1 and Foxa2 had overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+T-cells. Foxa1 and Foxa2 regulated expression of many genes encoding splicing-factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons (DEU). Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing-factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple DEU. Thus Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and that by also regulating splicing of splicing-factors, they exert widespread control of alternative splicing.

Type: Article
Title: The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dev.199754
Publisher version: https://doi.org/10.1242/dev.199754
Language: English
Additional information: © 2021. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Foxa1, Foxa2, Positive selection, RNA splicing, T-cell development, Thymus
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10130903
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