FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency.
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ABSTRACT:
SUBMITTER: Rota IA
PROVIDER: S-EPMC8641933 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
Publications
FOXN1 forms higher-order nuclear condensates displaced by mutations causing immunodeficiency.
Rota Ioanna A IA Handel Adam E AE Maio Stefano S Klein Fabian F Dhalla Fatima F Deadman Mary E ME Cheuk Stanley S Newman Joseph A JA Michaels Yale S YS Zuklys Saulius S Prevot Nicolas N Hublitz Philip P Charles Philip D PD Gkazi Athina Soragia AS Adamopoulou Eleni E Qasim Waseem W Davies Edward Graham EG Hanson Imelda I Pagnamenta Alistair T AT Camps Carme C Dreau Helene M HM White Andrea A James Kieran K Fischer Roman R Gileadi Opher O Taylor Jenny C JC Fulga Tudor T Lagerholm B Christoffer BC Anderson Graham G Sezgin Erdinc E Holländer Georg A GA
Science advances 20211203 49
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 w ...[more]
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Project description:The transcription factor FOXN1 is a master regulator of thymic epithelial cell development and function. Here we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multi-molecular 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 significantly altered in a patient's FOXN1 mutant 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, Foxn1, selectively impairs mouse thymic epithelial cell (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.
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