ZBTB48 is a priming factor regulating B-cell-specific CIITA expression
The class-II transactivator (CIITA) is the master regulator of MHC class-II gene expression and hence the adaptive immune response. Three cell type-specific promoters (pI, pIII, and pIV) are involved in the regulation of CIITA expression, which can be induced by IFN-γ in non-immune cells. While key regulatory elements have been identified within these promoters, our understanding of the transcription factors regulating CIITA expression is incomplete. Here, we demonstrate that the telomere-binding protein and transcriptional activator ZBTB48 directly binds to both critical activating elements within the B-cell-specific promoter CIITA pIII. ZBTB48 knockout impedes the CIITA/MHC-II expression program induced in non-APC cells by IFN-γ, and loss of ZBTB48 in mice silences MHC-II expression in pro-B and immature B cells. Transcriptional regulation of CIITA by ZBTB48 is enabled by ZBTB48-dependent chromatin opening at CIITA pIII upstream of activating H3K4me3 marks. We conclude that ZBTB48 primes CIITA pIII by acting as a molecular on-off-switch for B-cell-specific CIITA expression.
Authors
- Wai Khang Yong (ORCID: https://orcid.org/0000-0003-0872-9085)
- Vineeth Thachappilly Mukundan
- Yunyu Shi (ORCID: https://orcid.org/0000-0002-1348-4759)
- Arne Jahn (ORCID: https://orcid.org/0000-0003-1045-1908)
- Suman Wang
- Dennis Kappei (ORCID: https://orcid.org/0000-0002-3582-2253)
- Julia Hansen (ORCID: https://orcid.org/0000-0001-7828-1269)
- Michelle Meng Huang Mok (ORCID: https://orcid.org/0000-0001-7030-266X)
- Motomi Osato (ORCID: https://orcid.org/0000-0003-3982-9054)
- Vivian L. S. Kuan (ORCID: https://orcid.org/0000-0001-9547-0467)
- Vartika Khanchandani (ORCID: https://orcid.org/0000-0002-9331-3051)
- Ieva Norvaisaite
- Fudong Li (ORCID: https://orcid.org/0000-0002-2564-7826)
- Grishma Rane (ORCID: https://orcid.org/0000-0001-9674-4108)
- Naasyidah Zulkaflee
Institutions
- University of Science and Technology of China (CN)
- National University of Singapore (SG)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- National University Cancer Institute, Singapore (SG)
- National Center for Tumor Diseases (DE)
- University Hospital Carl Gustav Carus (DE)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s44318-024-00306-y
- Citations
- 6
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- National Research Foundation
- National Research Foundation Singapore
- Ministry of Education - Singapore
- Fritz Thyssen Stiftung
- Ministry of Education, India
- National Medical Research Council
- Cancer Science Institute of Singapore, National University of Singapore