A1 Refereed original research article in a scientific journal
A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation
Authors: Shetty Ankitha, Tripathi Subhash Kumar, Junttila Sini, Buchacher Tanja, Biradar Rahual, Bhosale Santosh D, Envall Tapio, Laiho Asta, Moulder Robert, Rasool Omid, Galande Sanjeev, Elo Laura L, Lahesmaa Riitta
Publisher: OXFORD UNIV PRESS
Publication year: 2022
Journal: Nucleic Acids Research
Journal name in source: NUCLEIC ACIDS RESEARCH
Journal acronym: NUCLEIC ACIDS RES
Volume: 50
Issue: 9
First page : 4938
Last page: 4958
Number of pages: 21
ISSN: 0305-1048
eISSN: 1362-4962
DOI: https://doi.org/10.1093/nar/gkac256
Web address : https://academic.oup.com/nar/article/50/9/4938/6574681
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/175412808
Th17 cells are essential for protection against extracellular pathogens, but their aberrant activity can cause autoimmunity. Molecular mechanisms that dictate Th17 cell-differentiation have been extensively studied using mouse models. However, species-specific differences underscore the need to validate these findings in human. Here, we characterized the human-specific roles of three AP-1 transcription factors, FOSL1, FOSL2 and BATF, during early stages of Th17 differentiation. Our results demonstrate that FOSL1 and FOSL2 co-repress Th17 fate-specification, whereas BATF promotes the Th17 lineage. Strikingly, FOSL1 was found to play different roles in human and mouse. Genome-wide binding analysis indicated that FOSL1, FOSL2 and BATF share occupancy over regulatory regions of genes involved in Th17 lineage commitment. These AP-1 factors also share their protein interacting partners, which suggests mechanisms for their functional interplay. Our study further reveals that the genomic binding sites of FOSL1, FOSL2 and BATF harbour hundreds of autoimmune disease-linked SNPs. We show that many of these SNPs alter the ability of these transcription factors to bind DNA. Our findings thus provide critical insights into AP-1-mediated regulation of human Th17-fate and associated pathologies.
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