MeCP2 Represses the Rate of Transcriptional Initiation of Highly Methylated Long Genes

Abstract

Highlights d MeCP2 represses transcription of highly methylated long genes through NCoR d Direct measurements of transcriptional initiation and elongation rates in the mouse brain d MeCP2 reduces transcriptional initiation, not elongation, of highly methylated long genes d Gene body-TSS contacts position distal MeCP2 molecules at the TSS

Quantitative analysis questions the role of MeCP2 as a global regulator of alternative splicing

“…In particular, our previous work [ 9 ] captured transcriptomic data sets in Lund Human Mesencephalic (LUHMES)-derived human dopaminergic neurons that expressed widely different levels of MeCP2, while total levels of DNA methylation remained constant. Additionally, Boxer et al [ 17 ] comprehensively captured transcriptomes and methylomes from wildtype ( WT ) and MeCP2 ( KO ) mouse brain tissues. To investigate the latter, we examined the Dnmt1/3a/3b triple-knockout mouse embryonic stem cells ( DNMT-TKO mESCs) that lack DNA methyltransferase activity [ 18 , 19 ].…”

“… (A) Cultured human neurons expressing multiple levels of MeCP2 [ 9 ] (B) Wildtype ( WT ) and MeCP2 Knockout ( KO ) brain tissue [ 17 ] (C) Pv and Vip neurons at 1 week, 3 weeks and 8 weeks [ 20 ] (D) DNMT-TKO and WT mESCs [ 18 ] (E) DNMT-TKO and WT mESCs [ 19 ] (F) Promyelocytes and Granulocytes [ 14 , 23 ]. See Table 1 for detailed information about data sets.…”

“…In some instances, the model fit is extremely poor, as evidenced by negative levels of splicing variation explained ( Fig 2A right panel). To recapitulate a similar situation in vivo , we used data sets from [ 17 ] which profiled transcriptomes and methylomes of WT and MeCP2 KO mouse brain tissues at very high sequencing depth. We found that DNA methylation levels, quantified from WGBS-seq, are statistically indistinguishable between WT and MeCP2 KO mice brains ( S4B and S4C Fig ): correlations between methylomes of different WT replicates are identical to correlations between methylomes in WT and KO samples.…”

DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopmental disorders

“…A critical function for mCA is to serve as a binding site for a neuron-enriched chromatin protein, Methyl-CpG binding Protein 2 (MeCP2) (Chen et al, 2015;Gabel et al, 2015;Guo et al, 2014). MeCP2 was initially defined by its high affinity for mCG, but biochemical and genomic studies indicate that it preferentially interacts with mCA to down-regulate transcription of genes with essential functions in the brain (Boxer et al, 2019;Gabel et al, 2015;Kinde et al, 2016;Lagger et al, 2017;Lyst and Bird, 2015). Loss of MeCP2 leads to the severe neurological disorder Rett syndrome, while duplication causes MeCP2duplication syndrome, an ASD, suggesting that read-out of mCA is critical to nervous system function (Amir et al, 1999;Van Esch et al, 2005).…”

Pervasive non-CpG methylation at zebrafish mosaic satellite repeats

“…Gene ontology (GO) analysis [15] of MOSAT motif-containing genes demonstrated a significant enrichment for terms associated with neuronal function and in particular synaptic function, in agreement with previous reports on neural mCH enrichment in mammals [4] (Additional File 1: Figure S4). Given the observation that long genes can be enriched and sensitive to mCH levels in mice and human brains [16,17], we investigated the length of MOSAT motif-containing genes and found them to be, on average, significantly longer than all genes as well as neural genes (Additional File 1: Figure S4). Moreover, MOSAT motif-containing genes do not appear to be constitutively expressed.…”