The Histone-H3K4-Specific Demethylase KDM5B Binds to Its Substrate and Product through Distinct PHD Fingers

Abstract

SUMMARY The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation. It contains three PHD fingers, the biological roles of which remain elusive. Here, we show that the first PHD1 finger of KDM5B binds unmodified histone H3, whereas the third PHD3 finger prefers the trimethylated mark, H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for a set of genes. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with HDAC1 in gene repression. Compared with the estrogen receptor positive breast cancers, KDM5B is downregulated in the triple-negative breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion ability, and the PHD1-H3K4me0 interaction is important for inhibition of migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a novel multivalent mechanism for KDM5B-mediated transcriptional regulation.

Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients

“…Thus, to confirm that IL-12B transcription is influenced by H3K4me3 methylation, we knocked down KDM5B by using siRNA. KDM5B is the enzyme responsible for demethylation of H3K4me3 (Klein et al 2014). We hypothesized that knocking down KDM5B will result in decreased demethylation of H3K4me3 leading to a higher transcription of IL-12B gene.…”

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

“…KDM5B is expressed at greater levels in breast cancer cells. H3K4me3 (Klein et al, 2014), while in MCF7 cells, KDM5B knockdown did not alter global H3K4me3 levels but did reduce H3K4me3 at specific genes (Li et al, 2011, Yamane et al, 2007. Over-expression of KDM5B in MDA-MB-231 cells suppressed the metastatic properties of these cells (Klein et al, 2014).…”

“…However, it is an interesting observation that all of the KDM5 family members are associated with HDAC1/2 (Li et al, 2011, Barrett et al, 2007, Tahiliani et al, 2007. KDM5B is associated with the HDAC1/2 NuRD complex (Klein et al, 2014, Li et al, 2011. It is also possible that the KDM5 family members are associated with the HDAC1/2, which is bound to RNA splicing factors (such as SRSF1 and SF3B1-4) .…”

Histone Demethylase Jumonji AT-rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes

“…In this study, we demonstrated that JARID1B is critical for the recruitment of GATA3 to the Foxa1 promoter and its transcriptional activation. As an H3K4me3/2 demethylase, JARID1B binding at the gene promoters can lead to decreased gene expression (19,39), but its recruitment to the intragenic regions (40) or enhancers (41) was shown to activate gene expression. In mammary epithelial cells, JARID1B loss induced a decrease rather than an increase in H3K4me3 levels at many of its target promoters.…”