MeCP2 regulates gene expression through recognition of H3K27me3

Abstract

MeCP2 plays a multifaceted role in gene expression regulation and chromatin organization. Interaction between MeCP2 and methylated DNA in the regulation of gene expression is well established. However, the widespread distribution of MeCP2 suggests it has additional interactions with chromatin. Here we demonstrate, by both biochemical and genomic analyses, that MeCP2 directly interacts with nucleosomes and its genomic distribution correlates with that of H3K27me3. In particular, the methyl-CpG-binding domain of MeCP2 shows preferential interactions with H3K27me3. We further observe that the impact of MeCP2 on transcriptional changes correlates with histone post-translational modification patterns. Our findings indicate that MeCP2 interacts with genomic loci via binding to DNA as well as histones, and that interaction between MeCP2 and histone proteins plays a key role in gene expression regulation.

MeCP2: latest insights fundamentally change our understanding of its interactions with chromatin and its functional attributes

“…Moreover, H3K27me3 is a landmark of facultative heterochromatin and hence the paper nicely and timely provides a link to the observations of the paper by Lee et al. [ 23 ] discussed above. In that paper, in addition to the binding of MeCP2 to H3K27me3, the authors also provide a very interesting analysis of the different chromatin fractions bound by MeCP2 in neurons (Figure 2).…”

“…[ 40 ] Also, using a high‐resolution analysis of MeCP2 ChiP‐seq data in mouse epithelial olfactory tissue predominantly enriched in a unique type of neurons (olfactory sensory neurons), distinct evidence was provided indicating that MeCP2 localizes in highly GC enriched chromatin regions irrespectively of their methylation or not. [ 41 ] In this regard, the interaction of MeCP2 with H3K27me3 independently of DNA methylation observed in the paper highlighted here, [ 23 ] represents the final nail to the coffin in this issue. The CpG enriched islands of the genome remain unmethylated yet, they are shored up by H3K27me3 [ 42,43 ] and unmethylated CpG islands ectopically inserted in the genome efficiently recruit H3K27me3.…”

“…[ 46 ] Thus, it is tentative to speculate that, while T158M likely maintains ACCP conformation with little effect on the binding of MeCP2 to H3K27me3, this will neither be the case for P152R or A140V; thus, impairing their ability to synergize with H3K9ac in the modulation of gene expression. [ 23 ]…”

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

“…This protein, initially thought to have repressor activity ( Nan et al, 1997 ), is now recognized to have both transcriptionally repressive and activating functions through its interaction with different cofactors ( Yasui et al, 2007 ; Chahrour et al, 2008 ). The protein is able to recognize (or read) DNA and histone methylation marks ( Lewis et al, 1992 ; Thambirajah et al, 2012 ; Lee et al, 2020 ) and, hence, it acts as a methylation-dependent transcriptional modulator within the context of chromatin ( Li et al, 2020 ). DNA methylation dysregulation is one of the hallmarks of diseases such as cancer ( Baylin and Jones, 2016 ), and MeCP2 mutations can alter the reading of this mark, as in RTT ( Kriaucionis and Bird, 2003 ), where it can impact the normal activity of cells.…”

Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity

“…Thus, levels of oxygen, iron, and metabolites can affect the stability of both 5mC and H3K27me3. Furthermore, the established 5mC reader protein, MeCP2, was recently shown to also bind to H3K27me3-enriched nucleosomes [ 49 ], illustrating conservation in the two transcription silencing mechanisms.…”