The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells

Kuo-Hsuan Hung; Yong H Woo; I-Ying Lin; Chin-Hsiu Liu; Li-Chieh Wang; Hsin-Yu Chen; Bor-Luen Chiang; Kuo-I Lin

doi:10.1093/nar/gky281

The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells

Nucleic Acids Res. 2018 Jun 20;46(11):5547-5560. doi: 10.1093/nar/gky281.

Authors

Kuo-Hsuan Hung¹, Yong H Woo², I-Ying Lin¹, Chin-Hsiu Liu^{1

3}, Li-Chieh Wang⁴, Hsin-Yu Chen¹, Bor-Luen Chiang^{4

5}, Kuo-I Lin¹

Affiliations

¹ Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
² Division of Biological Sciences, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
³ PhD Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Division of Allergy, Immunology and Rheumatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan.
⁴ Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan.
⁵ Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Abstract

T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / immunology*
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor Proteins / metabolism*
Cyclin-Dependent Kinase Inhibitor p18 / metabolism*
Epigenesis, Genetic / genetics
Histone Demethylases / metabolism*
Intracellular Signaling Peptides and Proteins
Jumonji Domain-Containing Histone Demethylases / metabolism*
Lupus Erythematosus, Systemic / pathology
Lymphocyte Activation / immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Protein Binding / genetics
Protein Tyrosine Phosphatases / metabolism*
Proteins / metabolism*
T-Lymphocytes, Helper-Inducer / immunology
Transcription Factor RelA / metabolism*
Up-Regulation / genetics

Substances

Cdkn2c protein, mouse
Cyclin-Dependent Kinase Inhibitor Proteins
Cyclin-Dependent Kinase Inhibitor p18
Intracellular Signaling Peptides and Proteins
Proteins
Rela protein, mouse
Transcription Factor RelA
Wdr5 protein, mouse
Histone Demethylases
JMJD2A protein, mouse
Jmjd2c protein, mouse
Jumonji Domain-Containing Histone Demethylases
Cdkn3 protein, mouse
Protein Tyrosine Phosphatases