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A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Medullary Thymic Epithelial Cell, Cell Culture

SUBMITTER: Philip Charles

LAB HEAD: Georg Hollander

PROVIDER: PXD025552 | Pride | 2021-10-29

REPOSITORIES: Pride

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			Action	DRS
	FL888_MSQ1344_20180515_IoannaRota_xL_1.pep.xml	Pepxml
	FL888_MSQ1344_20180515_IoannaRota_xL_1.raw	Raw
	FL888_MSQ1344_20180515_IoannaRota_xL_2.pep.xml	Pepxml
	FL888_MSQ1344_20180515_IoannaRota_xL_2.raw	Raw
	FL888_MSQ1344_20180515_IoannaRota_xL_3.pep.xml	Pepxml

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Disruption of higher order nuclear condensates by a dominant negative FOXN1 mutation causes immunodeficiency

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