PXD025552

PXD025552 is an original dataset announced via ProteomeXchange.

Title	A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency
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.
HostingRepository	PRIDE
AnnounceDate	2021-10-29
AnnouncementXML	Submission_2021-10-29_06:42:49.574.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Philip Charles
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-22 00:36:01	ID requested
⏵ 1	2021-10-29 06:42:49	announced

Dataset with its publication pending

submitter keyword: Forkhead box N1 transcription factor, immunodeficiency, thymus

Georg Hollander
contact affiliation	Department of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
contact email	georg.hollander@paediatrics.ox.ac.uk
lab head
Philip Charles
contact affiliation	University of Oxford
contact email	philip.charles@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025552
     1. Label: PRIDE project
     2. Name: A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency