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PXD048977

PXD048977 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleNon-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development
DescriptionOur 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.
HostingRepositoryPRIDE
AnnounceDate2024-05-23
AnnouncementXMLSubmission_2024-05-22_23:45:59.235.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD048977
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterTaehyeung Kim
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-01-29 07:37:46ID requested
12024-05-22 23:46:00announced
Publication List
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;
Keyword List
submitter keyword: Human, LC-MSMS, Jurkat
Contact List
Peter A Nigrovic
contact affiliationChief, Division of Immunology, Boston Children’s Hospital Professor of Pediatrics and Medicine
contact emailpeter.nigrovic@childrens.harvard.edu
lab head
Taehyeung Kim
contact affiliationBoston Childerns Hospital, Division of Immunology
contact emailtaehyeung.kim@childrens.harvard.edu
dataset submitter
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Dataset FTP location
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