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


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-?B 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.

SUBMITTER: Hung KH 

PROVIDER: S-EPMC6009645 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Hung Kuo-Hsuan KH   Woo Yong H YH   Lin I-Ying IY   Liu Chin-Hsiu CH   Wang Li-Chieh LC   Chen Hsin-Yu HY   Chiang Bor-Luen BL   Lin Kuo-I KI  

Nucleic acids research 20180601 11


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 prolife  ...[more]

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