Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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

PROVIDER: PRJNA682592 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

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

Project description:The transcription factor FOXN1 acts in a gene-dosage sensitive way as a master regulator of thymic epithelial cell development and maintenance enabling effective thymopoiesis. Its autosomal recessive loss of function is the molecular cause of the “nude” phenotype, a severe combined immunodeficiency caused by athymia. Here we report on a spontaneously occurring, novel heterozygous FOXN1 mutation that initially permits regular thymus organogenesis but results in a failure of thymic maintenance beyond late stages of human gestation. Modeling the mutation in mice results in divergent disruptions of normal TEC subtype differentiation and function. Transcriptionally inactive, the mutant disrupts the formation of wild type FOXN1 homo-multimers and occupies canonical DNA binding sites, at which it operates in a dominant negative fashion to displace wild type FOXN1 from nuclear condensates. Comparing the interactome of the mutant and wild type FOXN1 identified binding partners that uniquely interact with wild type FOXN1 and are characteristic constituents of nuclear organelles required for transcription. Mutant FOXN1 moves in and out of condensates over a time-course indistinguishable from that of wild type FOXN1, suggesting that the mutation did not affect the molecular movement of FOXN1. Thus, we have identified a clinically relevant gain of function mutation of FOXN1 that actively prevents the transcriptional activity of wild type FOXN1 and provides critical insight into the mechanism by which FOXN1 operates in controlling sustained gene expression necessary for normal thymic epithelial cell differentiation, maintenance and function.

2021-10-12 | GSE162668 | GEO

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

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.

2021-10-29 | PXD025552 | Pride

Higher-Order Organization Principles of Pre-translational mRNPs [RIPPLiT]

Project description:Higher-Order Organization Principles of Pre-translational mRNPs [RIPPLiT]

| PRJNA476057 | ENA

DNA methylation maintains integrity of higher order genome architecture

Project description:DNA methylation maintains integrity of higher order genome architecture

| PRJNA663616 | ENA

DNA methylation maintains integrity of higher order genome architecture (Nanopore)

Project description:DNA methylation maintains integrity of higher order genome architecture (Nanopore)

| PRJNA670129 | ENA

SETMAR regulates gene expression and modulates higher order chromatin structure

Project description:SETMAR regulates gene expression and modulates higher order chromatin structure

| PRJNA642400 | ENA

DNA methylation maintains integrity of higher order genome architecture (WGBS)

Project description:DNA methylation maintains integrity of higher order genome architecture (WGBS)

| PRJNA663620 | ENA

Gamma entrainment binds higher order brain regions and alleviates neurodegeneration

Project description:Gamma entrainment binds higher order brain regions and alleviates neurodegeneration

| PRJNA474231 | ENA

Co-opted transposons help perpetuate conserved higher-order chromosomal structures

Project description:Co-opted transposons help perpetuate conserved higher-order chromosomal structures

| PRJNA593858 | ENA

DNA methylation maintains integrity of higher order genome architecture (RNA-Seq)

Project description:DNA methylation maintains integrity of higher order genome architecture (RNA-Seq)

| PRJNA670159 | ENA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data