| First Author | Hung KH | Year | 2018 |
| Journal | Nucleic Acids Res | Volume | 46 |
| Issue | 11 | Pages | 5547-5560 |
| PubMed ID | 29718303 | Mgi Jnum | J:263804 |
| Mgi Id | MGI:6188768 | Doi | 10.1093/nar/gky281 |
| Citation | Hung KH, et al. (2018) The KDM4A/KDM4C/NF-kappaB and WDR5 epigenetic cascade regulates the activation of B cells. Nucleic Acids Res 46(11):5547-5560 |
| abstractText | 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-kappaB 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. |
