Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain

Abstract

The Mecp2 gene has been shown to be mutated in most cases of human Rett syndrome, and mouse models deleted for the ortholog have been generated. Lineage-specific deletion of the gene indicated that the Rett-like phenotype is caused by Mecp2 deficiency in neurons. Biochemical evidence suggests that Mecp2 acts as a global transcriptional repressor, predicting that mutant mice should have genome-wide transcriptional deregulation. We tested this hypothesis by comparing global gene expression in wild-type and Mecp2 mutant mice. The results of numerous microarray analyses revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, although statistical power analyses of the data indicated that even a small number of relatively subtle changes in transcription would have been detected if present. However, a classifier consisting of a combined small set of genes was able to distinguish between mutant and wild-type samples with high accuracy. This result suggests that Mecp2 deficiency leads to subtle gene expression changes in mutant brains which may be associated with the phenotypic changes observed.

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

“…However, cDNA microarray studies failed to detect large scale changes in transcriptional derepression in the brains of Mecp2 À/À mice. 32 There is therefore an emerging concept for a more gene selective role for MeCP2 involving regulation of a smaller number of key regulatory genes such as brain-derived neurotrophic factor (BDNF), a bona fida MeCP2 target. 33,34 However, this concept does not exclude gene selective or global regulatory functions for MeCP2 in non-neuronal cell types of the fully developed adult.…”

“…CBF-1 directly binds at an overlapping NF-kB (kB2)/CBF-1 site located at nucleotides À319 to À310 from the start site of transcription. 32 Interaction of CBF1 with MeCP2 located at methyl-CpG sites either 5 0 or 3 0 to the IkBa promoter (e.g. within exon 1/intron 1) and potentially located in distal regions of silent chromatin, will be facilitated by DNA/chromosome looping.…”

The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity

“…The discovery of MECP2 target genes, however, has proven a rather daunting task. Early-on large-scale expression arrays revealed only subtle changes in gene expression (Traynor et al, 2002;Tudor et al, 2002). Additional research into alternative functions of MECP2 suggests that the protein can also influence RNA splicing as well as activate gene expression (Chahrour et al, 2008;Lasalle and Yasui, 2009;Young et al, 2005).…”

Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes

“…Early studies suggest that MeCP2 bound to areas of particularly dense CpG dinucleotides or CpG islands and recruited histone HDACs and other factors involved in transcriptional silencing to nearby genes (7,8). More recent evidence suggests that Mecp2-null mice and Rett patients do not ectopically express genes that are regulated by promoter methylation (9,10). More diverse roles for MeCP2 have recently been shown in the direct compaction of chromatin (11,12) and the control of alternative splicing of pre-mRNA (13).…”