Sequence features accurately predict genome-wide MeCP2 binding in vivo

Rube, H. Tomas; Lee, Wooje; Hejna, Miroslav; Chen, Huaiyang; Yasui, Dag H.; Hess, John F.; LaSalle, Janine M.; Song, Jun S.; Gong, Qizhi

doi:10.1038/ncomms11025

Cited by 52 publications

(62 citation statements)

References 52 publications

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“…However, whether the selective binding of MECP2 to mCA sequences in different neuronal subtypes accounts for neuronal subtype-specific gene mis-regulation in RTT is not known. In mixed neuronal populations MECP2 has been shown to bind ubiquitously across the genome accumulating at near histone-octamer levels (Skene et al, 2010), and studies have suggested that MECP2 might bind to DNA to some extent regardless of the DNA methylation status (Baubec et al, 2013; Rube et al, 2016). Because accumulating evidence indicates that MECP2 binds avidly to mCA sequences in neurons to recruit the transcriptional co-repressor NCOR and thereby temper gene transcription, we asked whether MECP2 might function to enforce the neuronal subtype-specific dampening of the transcription of mCA-marked genes.…”

Section: Resultsmentioning

confidence: 99%

Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States

Stroud

Hrvatin

et al. 2017

Cell

174

241

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SUMMARY In mammals during the early postnatal period the environment plays a critical role in promoting the final steps in the neuronal development. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here we show that in the brain during early life the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. We find that DNMT3A occupancy and mCA deposition within the transcribed regions of genes is negatively regulated by gene transcription and may be modified by early-life experience. Once deposited, mCA is bound by the methyl-DNA-binding protein MECP2 and functions in a rheostat-like manner to fine-tune the cell type-specific transcription of genes that are critical for brain function.

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Section: Resultsmentioning

confidence: 99%

Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States

Stroud

Hrvatin

et al. 2017

Cell

174

241

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“…Taken together, these comparative data strongly suggest that the combination of analyzing both loss-of-function Mecp2 rodent models may provide a significant advantage for identifying transcriptional changes and likely other biochemical and molecular changes that occur in the human RTT brain that may not have been predicted in analyses of either rodent model alone. In the context of recent findings suggesting that MeCP2 may regulate the expression of long genes in a cell-type and brain-region specific manner (90,91), and preferentially bind to DNA at methylated cytosine at CG sites (92) yet also bind to methylated cytosine at non-CG sites (69) as well as nucleosomal sequences with high GC content alone (93), it would be highly informative to pursue similar studies using the Mecp2 rat model to further clarify the role of MeCP2 in the epigenetic regulation of gene expression and its impact on disease features of RTT and related disorders.…”

Section: Discussionmentioning

confidence: 96%

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

et al. 2016

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Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures.

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“…Contrasting with this conclusion, a recent study using olfactory bulb neurons, reported that MeCP2 is enriched at non-methylated CGIs and that DNA methylation is a minor determinant of binding [20]. This conflicts with the findings of our study and several previously published MeCP2 ChIP experiments, all of which found a dramatic drop in MeCP2 binding at CGIs in cultured cells [15], whole mouse brain [16], hypothalamus [27], cortex and cerebellum [26] coupled with DNA methylation-dependent occupancy of the genome.…”

Section: Discussionmentioning

confidence: 98%

MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain

et al. 2017

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Mutations in the gene encoding the methyl-CG binding protein MeCP2 cause several neurological disorders including Rett syndrome. The di-nucleotide methyl-CG (mCG) is the classical MeCP2 DNA recognition sequence, but additional methylated sequence targets have been reported. Here we show by in vitro and in vivo analyses that MeCP2 binding to non-CG methylated sites in brain is largely confined to the tri-nucleotide sequence mCAC. MeCP2 binding to chromosomal DNA in mouse brain is proportional to mCAC + mCG density and unexpectedly defines large genomic domains within which transcription is sensitive to MeCP2 occupancy. Our results suggest that MeCP2 integrates patterns of mCAC and mCG in the brain to restrain transcription of genes critical for neuronal function.

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Sequence features accurately predict genome-wide MeCP2 binding in vivo

Cited by 52 publications

References 52 publications

Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States

Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain

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