An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation

Abstract

We have previously described a multiprotein complex termed the BHC or BRAF-HDAC complex, which is required for the repression of neuronal-specific genes. We have shown that the BHC complex is recruited by a neuronal silencer, REST (RE1-silencing transcription factor), and mediates the repression of REST-responsive genes. BHC is a multiprotein complex consisting of two enzymatic activities: a histone deacetylase (HDAC1 or 2) and a recently described histone demethylase (BHC110, also known as LSD1 or AOF2). Here we show that BHC110-containing complexes show a nearly fivefold increase in demethylation of histone H3 lysine 4 (H3K4) compared to recombinant BHC110. Furthermore, recombinant BHC110 is unable to demethylate H3K4 on nucleosomes, but BHC110-containing complexes readily demethylate nucleosomes. In vitro reconstitution of the BHC complex using recombinant subunits reveals an essential role for the REST corepressor CoREST, not only in stimulating demethylation on core histones but also promoting demethylation of nucleosomal substrates. We find that nucleosomal demethylation is the result of CoREST enhancing the association between BHC110 and nucleosomes. Depletion of CoREST in in vivo cell culture results in de-repression of REST-responsive gene expression and increased methylation of H3K4. Together, these results highlight an essential role for CoREST in demethylation of H3K4 both in vitro and in vivo.

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

“…Interaction of retinoid receptors with b-catenin at the Id2 gene WRE presumably leads to recruitment of repressor complexes containing histone deacetylase and demethylase activities. Indeed, we were able to detect a retinoid-dependent recruitment to WRE in the Id2 gene promoter of LSD1 demethylase (Figure 5a), shown to be essential for histone H3 Lys-4 demethylation (Shi et al, 2004;Lee et al, 2005). As histone demethylases and deacetylases are believed to be present in non-related regulatory complexes, the observed pattern of histone modification at the Id2 gene implies sequential or independent recruitment to the WRE of different chromatin remodeling complexes.…”

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…HDAC1 and HDAC2 lack a DNA-binding domain, as do all deacetylases, and execute their function by interacting with transcription factors as either homo-or heterodimers, or being part of multi-component repressor complexes. 8,9 The best characterized HDAC1/2-containing complexes in mammals are the SIN3 co-repressor complex, 23 nucleosome remodeling and deacetylase (NuRD) complex, 24 CoREST complex, 25 Nanog and Oct4 (POU5F1)-associated deacetylase complex that is specifically found in embryonic stem (ES) cells, 26 and PRC2 complex. 27 The ubiquitous expression, high deacetylase activity toward common substrates and high homology between HDAC1 and HDAC2 suggest that each could compensate for loss of function of the other.…”

Structural dynamics of protein lysine methylation and demethylation

“…There are many examples of N(itrogen)-methylations (of arginine, lysine, glutamine, asparagine, histidine residues, and the amino group at the N terminus) in the cell. While it is not certain that all N-methylations are reversible, recent discoveries showed that a human nuclear peptidyl arginine deiminase, PAD4, antagonizes methylation on the arginine residues by converting arginine to citrulline [92][93][94] (Figure 5); a human nuclear amine oxidases, LSD1, functions as a histone di/mono-methyl-lysine demethylase via an oxidation reaction [95][96][97]; and JmjC domain-containing hydroxylase-like proteins are able to demethylate mono-, di-, or tri-methylated lysines [98,99], which was first proposed for S. pombe Epe1 [100].…”

“…Within these complexes, REST (RE1-silencing transcription factor) corepressor CoREST enables LSD1 to demethylate nucleosomes [96,97], while BHC80 (BRAF-HDAC complex) inhibits LSD1 activity [96]. The LSD1 polypeptide chain can be divided into several structural/ functional regions (Figure 6a): the N-terminal putative nuclear localization signal, followed by a SWIRM (Swi3p, Rsc8p, and Moira) domain (Figure 6b; [101])-found in several nucleosome-interacting proteins -and a monoamine oxidase domain -capable of demethylating lysines in an flavin-dependent manner [102].…”