Grishma Rane 1, Vivian L S Kuan 1, Suman Wang 2, Michelle Meng Huang Mok 1, Vartika Khanchandani 1, Julia Hansen 1, Ieva Norvaisaite 1, Naasyidah Zulkaflee 1, Wai Khang Yong 1, Arne Jahn 3 4 5 6, Vineeth T Mukundan 1, Yunyu Shi 2, Motomi Osato 1, Fudong Li 2, Dennis Kappei 7 8 9
Affiliations
- 1Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore.
- 2MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- 3Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
- 4National Center for Tumor Diseases (NCT), Dresden, Germany.
- 5German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 6ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany.
- 7Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore. dennis.kappei@nus.edu.sg.
- 8Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore, Singapore. dennis.kappei@nus.edu.sg.
- 9NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. dennis.kappei@nus.edu.sg.
Abstract
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.
