ZBTB48 is a priming factor regulating B-cell-specific CIITA expression

Grishma Rane; Vivian L S Kuan; Suman Wang; Michelle Meng Huang Mok; Vartika Khanchandani; Julia Hansen; Ieva Norvaisaite; Naasyidah Zulkaflee; Wai Khang Yong; Arne Jahn; Vineeth T Mukundan; Yunyu Shi; Motomi Osato; Fudong Li; Dennis Kappei

doi:10.1038/s44318-024-00306-y

ZBTB48 is a priming factor regulating B-cell-specific CIITA expression

EMBO J. 2024 Nov 19. doi: 10.1038/s44318-024-00306-y. Online ahead of print.

Authors

Grishma Rane¹, Vivian L S Kuan¹, Suman Wang², Michelle Meng Huang Mok¹, Vartika Khanchandani¹, Julia Hansen¹, Ieva Norvaisaite¹, Naasyidah Zulkaflee¹, Wai Khang Yong¹, Arne Jahn^{3

4

5

6}, Vineeth T Mukundan¹, Yunyu Shi², Motomi Osato¹, Fudong Li², Dennis Kappei^{7

8

9}

Affiliations

¹ Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore.
² MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
⁴ National Center for Tumor Diseases (NCT), Dresden, Germany.
⁵ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ ERN-GENTURIS, Hereditary Cancer Syndrome Center, Dresden, Germany.
⁷ Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore. dennis.kappei@nus.edu.sg.
⁸ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117596, Singapore, Singapore. dennis.kappei@nus.edu.sg.
⁹ NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. dennis.kappei@nus.edu.sg.

PMID: 39562739
DOI: 10.1038/s44318-024-00306-y

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.

Keywords: B Cell; CIITA; Epigenetics; Gene Expression; MHC II.

Abstract

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