Novel alterations in the epigenetic signature of MeCP2-targeted promoters in lymphocytes of Rett syndrome patients

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder with neurological symptoms, such as motor disorders and mental retardation. In most cases, RTT is caused by mutations in the DNA binding protein MeCP2. In mice, MeCP2 gene deletion has been reported to result in genome-wide increased histone acetylation. Transcriptional regulation of neurotrophic factor BDNF and transcription factor DLX5, essential for proper neurogenesis, is further altered in MeCP2-deleted animals. We therefore investigated the chromatin environment of MeCP2 target genes BDNF and DLX5 in lymphocytes from RTT patients and human controls, and analyzed the density of histones H3, H2B and H1, as well as the levels of methylation and acetylation on selected lysines of histone H3. Notably, we found a general increase in the density of histone H3 in RTT patients’ lymphocytes compared with controls, and decreased levels of trimethylation of lysine 4 on histone H3 (H3K4me3), a modification associated with transcriptional activation. The levels of acetylation of lysine 9 (H3K9ac) and 27 (H3K27ac) did not show any statistically significant changes when normalized to the decreased histone H3 levels; nevertheless, an average decrease in acetylation was noted. Our results reveal an unexpected alteration of the chromatin state of established MeCP2 target genes in lymphocytes of human subjects with RTT.

Epigenetic Findings in Autism: New Perspectives for Therapy

“…Rett syndrome (RTT), a disease caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2), is associated to defects in epigenetic modifiers [72]. RTT patients show alteration of the chromatin state of MeCP2 target genes: increase in the density of histone H3 and decreased levels of trimethylation of lysine 4 on histone H3 (H3K4me3), a modification associated with transcriptional activation [73]. …”

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…MeCP2-mediated transcriptional repression may involve two distinct mechanisms one being dependent on chromatin modification by histone deacetylation and the other being chromatin independent (block transcription factors directly) [149][150][151]. In RTT patients' lymphocytes compared with controls have been shown to be increased in the density of histone H3, and decreased levels of trimethylation of lysine 4 on histone H3 (H3K4me3), a modification associated with transcriptional activation [152]. MeCP2 results in the alteration of the chromatin state by suppressing a number of target genes associated with synaptic function and disrupted synaptic plasticity mechanisms (e.g., BDNF, DLX5, ID, CRH, IGFBP3, CDKL1, PCDHB1, and PCDH7, LIN7A) in neurons and other types of brain cells [153,154].…”

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