Projects per year
Abstract
The transcription factor FOXN1 is a master regulator of thymic epithelial cell (TEC) development and function. Here, we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multimolecular nuclear condensates essential for the factor’s transcriptional activity. FOXN1’s C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are altered in a patient with a mutant FOXN1 that is modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog selectively impairs mouse TEC differentiation, revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect.
Original language | English |
---|---|
Article number | eabj9247 |
Number of pages | 19 |
Journal | Science Advances |
Volume | 7 |
Issue number | 49 |
DOIs | |
Publication status | Published - 3 Dec 2021 |
Bibliographical note
Acknowledgments:We thank R. Geha and T. Barthlott for helpful discussions and G. Riddihough (LSE) for editorial assistance. We thank S. Palmer for generating the graph in fig. S7F. Funding: This work was supported by Swiss National Science Foundation (IZLJZ3_171050; 310030_184672) and the Wellcome Trust (105045/Z/14/Z) to G.A.H.; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) to G.A.H.; departmental stipend (Department of Paediatrics, University of Oxford) to I.A.R.; NIHR Clinical Lectureship to A.E.H.; Wellcome Trust (109032/Z/15/Z) and an NIHR Clinical Lectureship to F.D.; International postdoc fellowship from the Swedish research council (Vetenskapsrådet) to S.C.; Swiss National Science Foundation–Early Postdoc.Mobility Fellowship–P2BSP3_188183 to F.K.; SciLifeLab Fellowship and Swedish Research Council Starting Grant (2020-02682) to E.S.; Wellcome Trust and Department of Health as part of a Health Innovation Challenge Fund scheme grant (Wellcome Core Award grant number 203141/Z/16/Z) to J.C.T., A.T.P., and C.C. as part of the The OxClinWGS Study Health Innovation Challenge Fund (R6-388/WT 100127), a parallel funding partnership between the Wellcome Trust, the Department of Health to J.C.T.; and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) to J.C.T., A.T.P., and C.C. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health or Wellcome Trust. This work was also supported by MRC Programme Grant (MR/T029765/1) to G.A. NIHR (RP-2014-05-007); the Great Ormond Street Hospital Biomedical Research Centre to W.Q., E.G.D., and A.S.G.; and a Wellcome trust grant 106169/ZZ14/Z to O.G. and J.A.N.
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
ASJC Scopus subject areas
- General
Fingerprint
Dive into the research topics of 'FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency'. Together they form a unique fingerprint.Projects
- 1 Active
-
Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production
Anderson, G. (Principal Investigator)
1/01/21 → 31/08/26
Project: Research Councils