RT Journal Article
SR Electronic
T1 A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.28.437237
DO 10.1101/2021.03.28.437237
A1 Ioanna A. Rota
A1 Adam E. Handel
A1 Fabian Klein
A1 Stefano Maio
A1 Fatima Dhalla
A1 Mary E. Deadman
A1 Stanley Cheuk
A1 Joseph A Newman
A1 Yale S. Michaels
A1 Saulius Zuklys
A1 Nicolas Prevot
A1 Philip Hublitz
A1 Philip D. Charles
A1 Athina Soragia Gkazi
A1 Eleni Adamopoulou
A1 Waseem Qasim
A1 E. Graham Davies
A1 Celine Hanson
A1 Alistair T. Pagnamenta
A1 Carme Camps
A1 Helene M. Dreau
A1 Andrea White
A1 Kieran James
A1 Roman Fischer
A1 Opher Gileadi
A1 Jenny C. Taylor
A1 Tudor Fulga
A1 B. Christoffer Lagerholm
A1 Graham Anderson
A1 Erdinc Sezgin
A1 Georg A. Holländer
YR 2021
UL http://biorxiv.org/content/early/2021/03/29/2021.03.28.437237.abstract
AB 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 with a mutant FOXN1 which 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 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.Competing Interest StatementThe authors have declared no competing interest.