title: Epigenetic silencing of V(D)J recombination is a major determinant for selective differentiation of mucosal-associated invariant t cells from induced pluripotent stem cells.
abstract: Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine. However, the molecular mechanisms underlying this phenomenon remain unclear. Here, we performed methylome and transcriptome analyses of MAITs during the course of differentiation from iPSCs. Our multi-omics analyses revealed that recombination-activating genes (RAG1 and RAG2) and DNA nucleotidylexotransferase (DNTT) were highly methylated with their expression being repressed throughout differentiation. Since these genes are essential for V(D)J recombination of the T cell receptor (TCR) locus, this indicates that nascent MAITs are kept from further rearrangement that may alter their antigen specificity. Importantly, we found that the repression of RAGs was assured in two layers: one by the modulation of transcription factors for RAGs, and the other by DNA methylation at the RAG loci. Together, our study provides a possible explanation for the unaltered antigen specificity in the selective differentiation of MAITs from iPSCs.
authors.affiliation: Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Koto-ku, Tokyo, Japan.|Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Shinjuku-ku, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.
authors.forename: Yutaka
authors.identifier: http://orcid.org/0000-0002-4853-0153
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Hygiene and Cellular Preventive Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Sugimoto
authors.affiliation: Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Koto-ku, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.
authors.forename: Toutai
authors.initials: T
authors.lastname: Mituyama
authors.affiliation: Department of Hygiene and Cellular Preventive Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakao
mesh_terms: D002454:Cell Differentiation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D020868:Gene Silencing; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D000072336:Mucosal-Associated Invariant T Cells / Q000166:cytology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D059467:Transcriptome; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D011948:Receptors, Antigen, T-Cell