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

• Published in: The EMBO journal Vol. 43; no. 24; pp. 6236 - 6263
• Main Authors: Rane, Grishma, Kuan, Vivian L S, Wang, Suman, Mok, Michelle Meng Huang, Khanchandani, Vartika, Hansen, Julia, Norvaisaite, Ieva, Zulkaflee, Naasyidah, Yong, Wai Khang, Jahn, Arne, Mukundan, Vineeth T, Shi, Yunyu, Osato, Motomi, Li, Fudong, Kappei, Dennis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2024
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomedical and Life Sciences; EMBO09; EMBO19; Gene Expression Regulation; Humans; Interferon-gamma - genetics; Interferon-gamma - metabolism; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Promoter Regions, Genetic; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Epigenetics; MHC II; CIITA; B Cell; Gene Expression
• ISSN: 1460-2075; 0261-4189; 1460-2075
• DOI: 10.1038/s44318-024-00306-y

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. Synopsis Expression of CIITA, the master regulator of MHC-II expression, is governed by three cell type-specific promoters. This study identifies ZBTB48 as a priming factor for CIITA promoter III (pIII) enabling both constitutive expression in B-cells and IFN-γ-induced expression in non-APC cells. ZBTB48 directly binds two critical activating elements in the B-cell-specific promoter III of CIITA. ZBTB48 mediates both IFN-γ-induced CIITA pIII expression in non-APC cells and constitutive expression in B-cells in vivo. ZBTB48 promotes chromatin opening at CIITA pIII and acts as a priming factor. ZBTB48 binds to the B-cell-specific promoter CIITA pIII and regulates expression of CIITA and MHC-II by promoting chromatin opening.