Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A

Abstract

Human lysine demethylase KDM5A is a chromatin-modifying enzyme associated with transcriptional regulation, because of its ability to catalyze removal of methyl groups from methylated lysine 4 of histone H3 (H3K4me3). Amplification of KDM5A is observed in many cancers, including breast cancer, prostate cancer, hepatocellular carcinoma, lung cancer, and gastric cancer. In this study, we employed alanine scanning mutagenesis to investigate substrate recognition of KDM5A and identify the H3 tail residues necessary for KDM5A-catalyzed demethylation. Our data show that the H3Q5 residue is critical for substrate recognition by KDM5A. Our data also reveal that the protein-protein interactions between KDM5A and the histone H3 tail extend beyond the amino acids proximal to the substrate mark. Specifically, demethylation activity assays show that deletion or mutation of residues at positions 14-18 on the H3 tail results in an 8-fold increase in the K M app , compared to wild-type 18mer peptide, suggesting that this distal epitope is important in histone engagement. Finally, we demonstrate that posttranslational modifications on this distal epitope can modulate KDM5A-dependent demethylation. Our findings provide insights into H3K4-specific recognition by KDM5A, as well as how chromatin context can regulate KDM5A activity and H3K4 methylation status.

ELK4 promotes the development of gastric cancer by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis

“…Intriguingly, ELK4 can regulate cellular homeostasis and stress responses in macrophages to affect acute responses to external infection [ 7 ]. Lysine-specific demethylase 5A (KDM5A/RBP2) is identified as a chromatin-modifying enzyme related to transcriptional regulation by catalyzing removal of methyl groups from methylated lysine 4 of histone H3 and this gene is observed in multiple cancers including GC [ 8 ]. As previously reported, suppression of KDM5A by microRNA-212 could result in inhibited GC proliferation [ 9 ].…”

Histone demethylase KDM5A regulates the functions of human periodontal ligament stem cells during periodontitis via the miR-495-3p/HOXC8 axis

“…According to the literature, KDM5A as the H3K4Me3 demethylase [ 14 ] could bind to the miR-495 promoter to inhibit the transcription and expression of miR-495 [ 18 ]. Therefore, we hypothesized that KDM5A influences miR-495-3p transcription via H3K4me3.…”

“…The results are supported by previous studies proposing that miR-495-3p and H3K4me3 have weak expressions in periodontal diseases [ 37 , 38 ]. Furthermore, a previous study has evidenced that KDM5A catalyzed methylation of H3K4me3 [ 14 ]. After downregulation of KDM5A, the levels of H3K4me3 and miR-495-3p were both reduced, suggesting that KDM5A regulated the miR-495-3p expression via H3K4me3.…”

“…Histone demethylases could act as epigenetic regulators for the treatment of various diseases and cancers [ 11 , 12 ]. Especially, KDM5A could catalyze the demethylation of methylated lysine 4 of histone H3 (H3K4me3) and plays a negative role in osteogenic differentiation (OD) during osteoporosis [ 13 , 14 ]. The role of histone demethylase KDM5A in the functions of hPDLSCs has not been reported at home and abroad.…”

Evaluation of Jumonji C lysine demethylase substrate preference to guide identification of in vitro substrates

“…Although this has been shown to be the case for many KMT enzymes, and for Suv39H2 the +5 position also determines specificity ( Schuhmacher et al., 2015 ), recognition of substrates may also be determined by more distant interactions. Additionally, on the H3 tail, more distal sequence elements were recently shown to be important for KDM5A-dependent demethylation of the H3-K4 site ( Petronikolou et al., 2020 ).…”