PXD048977

PXD048977 is an original dataset announced via ProteomeXchange.

Title	Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development
Description	Our fine-mapping of 76 non-MHC loci associated with risk for rheumatoid arthritis (RA, 11,475 cases, 15,870 controls) has recently identified rs117701653, a non-coding single nucleotide polymorphism (SNP) in the CTLA4/CD28/ICOS locus, as the variant most likely to modulate RA risk within this region, with the minor allele (C) showing disease protection compared to the major allele (A). Notably, this SNP exhibits allele-specific protein binding, further supporting its regulatory nature, including greater binding of proteins from Jurkat T cell nuclear extract to the protective allele (C) than to the risk allele (A) by electrophoretic mobility shift assay (EMSA). To identify this protein or protein complex, we applied an efficient DNA pulldown technique, flanking restriction enhanced pulldown (FREP), using nuclear extract from Jurkat T cells, bait DNA corresponding to the (C) allele of rs117701653, competitor DNA fragment, and irrelevant DNA sequence as a negative control. Mass spectrometry analysis of peptides released from FREP identified 43 proteins. Our strongest candidate was structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1), which exhibited specific binding to the (C) allele of rs117701653. We confirmed the allelic affinity of SMCHD1 using multiple orthogonal approaches, including FREP and western blotting, EMSA with anti-SMCHD1 antibodies, and CHIP-qPCR with CRISPR-modified Jurkat clones bearing different genotype at rs117701653. In this study, we identified SMCHD1, a chromatin regulator that binds allelically to the rs117701653 allele (C) associated with protection against RA risk.
HostingRepository	PRIDE
AnnounceDate	2024-05-23
AnnouncementXML	Submission_2024-05-22_23:45:59.235.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD048977
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Taehyeung Kim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-29 07:37:46	ID requested
⏵ 1	2024-05-22 23:46:00	announced

Kim T, Mart, í, nez-Bonet M, Wang Q, Hackert N, Sparks JA, Baglaenko Y, Koh B, Darbousset R, Laza-Briviesca R, Chen X, Aguiar VRC, Chiu DJ, Westra HJ, Gutierrez-Arcelus M, Weirauch MT, Raychaudhuri S, Rao DA, Nigrovic PA, Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development. Nat Commun, 15(1):2150(2024) [pubmed]

10.6019/PXD048977;

10.1038/s41467-024-46457-8;

submitter keyword: Human, LC-MSMS, Jurkat

Peter A Nigrovic
contact affiliation	Chief, Division of Immunology, Boston Children’s Hospital Professor of Pediatrics and Medicine
contact email	peter.nigrovic@childrens.harvard.edu
lab head
Taehyeung Kim
contact affiliation	Boston Childerns Hospital, Division of Immunology
contact email	taehyeung.kim@childrens.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD048977

PRIDE project URI

• PRIDE
  1. PXD048977
     1. Label: PRIDE project
     2. Name: Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development