慶應義塾研究者情報データベース

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• Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.

  Tian C, Zhang Y, Tong Y, Kock KH, Sim DY, Liu F, Dong J, Jing Z, Wang W, Gao J, Tan LM, Han KY, Tomofuji Y, Nakano M, Buyamin EV, Sonthalia R, Ando Y, Hatano H, Sonehara K, Asian Immune Diversity Atlas Network, Jin X, Loh M, Chambers J, Hon CC, Choi M, Park JE, Ishigaki K, Okamura T, Fujio K, Okada Y, Park WY, Shin JW, Roca X, Prabhakar S, Liu B

  Nature genetics 56 （ 12 ） 2739 - 2752 2024年12月

  ISSN  1061-4036

  　概要を見る

  Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5' splice site of TCHP exon 4 that putatively modulates the risk of Graves' disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.

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• Dynamic Manipulation of Non-Hermitian Skin Effect through Frequency in Topolectrical Circuits

  S M Rafi-Ul-Islam, Zhuo Bin Siu, Md. Saddam Hossain Razo, Mansoor B. A. Jalil

  2024年10月

  　概要を見る

  One of the most fascinating phenomena in non-Hermitian systems is the extensive accumulation of the bulk eigenstates under open-boundary conditions which is known as the non-Hermitian skin effect (NSHE). Here, we propose a switchable NHSE in a topolectrical (TE) set-up which can be turned on or off simply by varying the driving frequency without any modification to the physical circuit. Specifically, we consider a coupled system consisting of two non-Hermitian Hatano-Nelson chains where each node of one chain is connected to neighboring node of the other chain via resistive couplings with opposite signs for the two coupling directions. Interestingly, the NHSE is switched on only if the driving frequency is greater than a certain critical frequency. Conversely, the NHSE in the coupled system is switched off when the frequency falls below the critical value, even though the individual uncoupled chains still exhibit the NHSE. This frequency-controlled NHSE may pave the way for many possible applications including non-Hermitian sensors where the driving frequency can manipulate the current and voltage localization.

• Epigenetic targets of Janus kinase inhibitors are linked to genetic risks of rheumatoid arthritis.

  Tsuchiya H, Ota M, Takahashi H, Hatano H, Ogawa M, Nakajima S, Yoshihara R, Okamura T, Sumitomo S, Fujio K

  Inflammation and regeneration 44 （ 1 ） 29 - 29 2024年06月

  ISSN  1880-9693

  　概要を見る

  BACKGROUND: Current strategies that target cytokines (e.g., tumor necrosis factor (TNF)-α), or signaling molecules (e.g., Janus kinase (JAK)) have advanced the management for allergies and autoimmune diseases. Nevertheless, the molecular mechanism that underpins its clinical efficacy have largely remained elusive, especially in the local tissue environment. Here, we aimed to identify the genetic, epigenetic, and immunological targets of JAK inhibitors (JAKis), focusing on their effects on synovial fibroblasts (SFs), the major local effectors associated with destructive joint inflammation in rheumatoid arthritis (RA). METHODS: SFs were activated by cytokines related to inflammation in RA, and were treated with three types of JAKis or a TNF-α inhibitor (TNFi). Dynamic changes in transcriptome and chromatin accessibility were profiled across samples to identify drug targets. Furthermore, the putative targets were validated using luciferase assays and clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. RESULTS: We found that both JAKis and the TNFi targeted the inflammatory module including IL6. Conversely, specific gene signatures that were preferentially inhibited by either of the drug classes were identified. Strikingly, RA risk enhancers for CD40 and TRAF1 were distinctively regulated by JAKis and the TNFi. We performed luciferase assays and CRISPR-based genome editing, and successfully fine-mapped the single causal variants in these loci, rs6074022-CD40 and rs7021049-TRAF1. CONCLUSIONS: JAKis and the TNFi had a direct impact on different RA risk enhancers, and we identified nucleotide-resolution targets for both drugs. Distinctive targets of clinically effective drugs could be useful for tailoring the application of these drugs and future design of more efficient treatment strategies.

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• Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms.

  Inamo J, Suzuki A, Ueda MT, Yamaguchi K, Nishida H, Suzuki K, Kaneko Y, Takeuchi T, Hatano H, Ishigaki K, Ishihama Y, Yamamoto K, Kochi Y

  Nature communications （Springer Nature）  15 （ 1 ） 4285 - 4285 2024年05月

  　概要を見る

  Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer’s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.

  • Access to Document (DOI)
  • CiNii Research

• Age-associated CD4(+) T cells with B cell-promoting functions are regulated by ZEB2 in autoimmunity.

  Goto M, Takahashi H, Yoshida R, Itamiya T, Nakano M, Nagafuchi Y, Harada H, Shimizu T, Maeda M, Kubota A, Toda T, Hatano H, Sugimori Y, Kawahata K, Yamamoto K, Shoda H, Ishigaki K, Ota M, Okamura T, Fujio K

  Science immunology （American Association for the Advancement of Science (AAAS)）  9 （ 93 ） eadk1643 2024年03月

  　概要を見る

  <jats:p>
  Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4
  <jats:sup>+</jats:sup>
  T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3
  <jats:sup>mid</jats:sup>
  CD4
  <jats:sup>+</jats:sup>
  effector memory T cell subset that expands with age, which we designated “age-associated T helper (T
  <jats:sub>H</jats:sub>
  A) cells.” T
  <jats:sub>H</jats:sub>
  A cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of T
  <jats:sub>H</jats:sub>
  A cells, gene expression in T
  <jats:sub>H</jats:sub>
  A cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that T
  <jats:sub>H</jats:sub>
  A cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of T
  <jats:sub>H</jats:sub>
  A cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.
  </jats:p>

  • Access to Document (DOI)
  • CiNii Research

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