Functional Interplay between Histone Demethylase and Deacetylase Enzymes

Abstract

Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Here we show that HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by BHC110 in vitro. In vivo analysis revealed an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used. Importantly, while the enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro, in vivo analysis following ectopic expression of an enzymatically dead mutant of BHC110 (K661A) confirmed the functional cross talk between the demethylase and deacetylase enzymes. Our studies not only reveal an intimate link between the histone demethylase and deacetylase enzymes but also identify histone demethylation as a secondary target of HDAC inhibitors.

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

“…2d,e). Next, we addressed whether the demethylase activity of Lsd1 is required for directing TSC fate by ectopic expression of a catalytic inactive mutant of Lsd1 (Lsd1 Mut ) 30 . Ectopic expression of the Lsd1 mutant protein in Lsd1 À / À TSCs does not alter the transcription of stem cellassociated genes such as Eomes (Supplementary Fig.…”

HISTONE DEACETYLASE6 Interacts with FLOWERING LOCUS D and Regulates Flowering in Arabidopsis

“…Although cross talk between histone deacetylation and demethylation has previously been suggested to modulate gene expression in mammalian cells (Shi et al, 2005;Lee et al, 2006), the direct association of a HDAC with a histone demethylase has not been reported. In this study, we found that HDA6 physically associates with FLD in vitro and in vivo, indicating that these two proteins act in the same protein complex.…”

“…The peripheral zone of the nucleus is the area that has been implicated in the regulation of gene expression, especially gene silencing (Deniaud and Bickmore, 2009). The mammalian histone demethylase, LSD1, is an integral component of histone deacetylase corepressor complexes, in which HDACs and LSD1 may cooperate to remove activating acetyl and methyl histone modifications (Shi et al, 2005;Lee et al, 2006). HDAC inhibitors can diminish histone demethylation activity, whereas the abrogation of LSD1 activity by mutations can decrease deacetylation activity (Lee et al, 2006), suggesting that the enzymatic activities of HDACs and LSD1 are closely linked.…”

“…The mammalian histone demethylase, LSD1, is an integral component of histone deacetylase corepressor complexes, in which HDACs and LSD1 may cooperate to remove activating acetyl and methyl histone modifications (Shi et al, 2005;Lee et al, 2006). HDAC inhibitors can diminish histone demethylation activity, whereas the abrogation of LSD1 activity by mutations can decrease deacetylation activity (Lee et al, 2006), suggesting that the enzymatic activities of HDACs and LSD1 are closely linked. Further research is required to determine whether there is a synergistic interplay between histone demethylase and deacetylase activities in plants.…”

dCas9: A Versatile Tool for Epigenome Editing

“…LSD1: Lysine-specific demethylase 1 (LSD1) demethylates histone 3 at lysine residues 4 and 9, leading to silencing of enhancers (Shi et al, 2004). LSD1 functionally interacts with other chromatinmodifying enzymes, including histone deacetylases that remove acetyl groups from histone 3 at lysine residue 27 (Lee et al, 2006).…”