Identification of conserved cis-regulatory elements impact Mecp2 level and neurological functions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA640181 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12044363_1.fastq.gz | Fastqsanger.gz | |||
| SRR12044363_2.fastq.gz | Fastqsanger.gz | |||
| SRR12044364_1.fastq.gz | Fastqsanger.gz | |||
| SRR12044364_2.fastq.gz | Fastqsanger.gz | |||
| SRR12044365_1.fastq.gz | Fastqsanger.gz |
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Project description:Methyl-CpG binding protein 2 (MeCP2) is a nuclear protein that binds to methylated cytosines and regulates gene expression. Normal brain function requires precise control of MeCP2 level. Loss of function mutations in the X-linked gene, MECP2 cause Rett Syndrome (RTT), a progressive neurological disorder. Increase in MeCP2 level leads to the neurological disorder MECP2 duplication syndrome (MDS). Despite the functional importance of MeCP2 in the brain, its transcriptional regulation remains poorly understood. Here, we utilized ATAC-seq in the mouse brain across development to identify five putative adult brain cis-regulatory elements (CREs) of Mecp2. We found that knocking out these CREs using CRISPR-Cas9 altered Mecp2 levels. Furthermore, two of the CREs were conserved in human, and when we delete either of these in mice, the animals show progressive neurological dysfunction. Deletion of one of the conserved CREs led to a decreased MeCP2 level and caused phenotypes similar, albeit milder, to those seen in Mecp2-null mice whereas the deletion of the second CRE led to an increased MeCP2 level and phenotypically resembled, but also milder than, MECP2 duplication mice. Deleting these two conserved CREs levels in human iPSC-derived neurons also similarly altered MECP2 levels. Taken together, our discovery of CREs that modulate Mecp2/MECP2 expression provides insight into regulation of Mecp2/MECP2 in the mouse brain and human neurons, respectively. These CREs could be candidate sites for non-coding mutations that lead to neurodevelopmental disorders characterized by partial features of RTT or MDS.
2020-12-01 | GSE152719 | GEO
Project description:While changes in MeCP2 dosage cause Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), its transcriptional regulation is poorly understood. Here, we identified six putative noncoding regulatory elements of Mecp2, two of which are conserved in humans. Upon deletion in mice and human iPSC-derived neurons, these elements altered RNA and protein levels in opposite directions and resulted in a subset of RTT- and MDS-like behavioral deficits in mice. Our discovery provides insight into transcriptional regulation of Mecp2/MECP2 and highlights genomic sites that could serve as diagnostic and therapeutic targets in RTT or MDS.
| S-EPMC8015713 | biostudies-literature
Project description:Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett Syndrome. As a chromatin associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. While neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here we report the identification of several novel MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors. E 15.5 Mecp2 -/y cortical neurons were infected with lentivirus expressing wild-type and S80A mutant MeCP2 at similar protein expression level. 2 biological independent samples and dye swap were used for this set (GSM367413) and replicate 2 set (GSM367414).
2009-02-10 | E-GEOD-14715 | biostudies-arrayexpress
Project description:Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett Syndrome. As a chromatin associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. While neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here we report the identification of several novel MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors.
2009-02-10 | GSE14715 | GEO
Project description:A unique signature of neuronal transcriptomes is the high expression of the longest genes in the genome (e.g. >100 kilobases). These genes encode proteins with essential functions in neuronal physiology, and disruption of long gene expression has been implicated in neurological disorders. DNA topoisomerases resolve topological constraints that arise on DNA and facilitate the expression of long genes in neurons. Conversely, methyl-CpG binding protein 2 (MeCP2), which is disrupted in Rett syndrome, can act as a transcriptional repressor to downregulate the expression of long genes. The molecular mechanisms underlying the regulation of long genes by these factors are not fully understood, however, and whether or not they directly influence each other is not known. Here, we identify a functional interaction between MeCP2 and Topoisomerase II-beta (TOP2β) in neurons. We show that MeCP2 and TOP2β physically interact in vivo and map protein sequences sufficient for their physical interaction in vitro. We profile TOP2β activity genome-wide in neurons and detect enrichment at regulatory regions and gene bodies of long neuronal genes, including long genes regulated by MeCP2. Further, we find that knockdown and overexpression of MeCP2 leads to altered TOP2β activity at MeCP2-regulated genes. Our findings uncover a mechanism by which MeCP2 inhibits the activity of TOP2β at long genes in neurons and suggest that this mechanism is disrupted in neurodevelopment disorders caused by mutation of MeCP2.
2023-11-15 | PXD046904 | Pride
Project description:Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that is proposed to function as a transcriptional repressor, but, despite numerous studies examining neuronal gene expression in MeCP2 mutants, no coherent model has emerged for how MeCP2 regulates transcription. Here we identify a genome-wide length-dependent increase in the expression of long genes in neurons lacking MeCP2. This gene misregulation occurs in human RTT brains and correlates with onset and severity of phenotypes in Mecp2 mutant mice, suggesting that the disruption of long gene expression contributes to RTT pathology. We present evidence that MeCP2 represses long genes by binding to brain-enriched, methylated CA dinucleotides within genes and show that loss of methylated CA in the brain recapitulates gene expression defects observed in MeCP2 mutants. We find that long genes encode proteins with neuronal functions, and overlap substantially with genes that have been implicated in autism and Fragile X syndrome. Reversing the overexpression of long genes in neurons lacking MeCP2 can improve some RTT-associated cellular deficits. These findings suggest that a function of MeCP2 in the mammalian brain is to temper the expression of genes in a length-dependent manner, and that mutations in MeCP2 and possibly other autism genes may cause neurological dysfunction by disrupting the expression of long genes in the brain.
2015-03-12 | GSE60074 | GEO
Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome. We previously found that Mecp2-null microglia are deficient in phagocytic ability, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. We have observed that Mecp2 deficiency is associated with increased levels of histone acetylation at the cis-regulatory regions of the Mecp2-regulated genes in macrophages. We hypothesized that Mecp2 recruits protein complexes containing histone deacetylases (HDACs) to repress the expression of its target genes. Our ChIP-Seq studies in bone-marrow derived macrophages revealed that Mecp2 co-localizes with Ncor2/Hdac3 protein complex at cis-regulatory regions of the target genes. These results suggest a role for Mecp2 in the recruitment and regulation of Ncor2/Hdac3 repressosome that plays a critical role in the regulation of inflammatory responses in macrophages. Examination of NCOR2 and HDAC3 genome-wide location in bone-marrow derived macrophages.
2015-03-31 | E-GEOD-66501 | biostudies-arrayexpress
Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome. We previously found that Mecp2-null microglia are deficient in phagocytic ability, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. We have observed that Mecp2 deficiency is associated with increased levels of histone acetylation at the cis-regulatory regions of the Mecp2-regulated genes in macrophages. We hypothesized that Mecp2 recruits protein complexes containing histone deacetylases (HDACs) to repress the expression of its target genes. Our ChIP-Seq studies in bone-marrow derived macrophages revealed that Mecp2 co-localizes with Ncor2/Hdac3 protein complex at cis-regulatory regions of the target genes. These results suggest a role for Mecp2 in the recruitment and regulation of Ncor2/Hdac3 repressosome that plays a critical role in the regulation of inflammatory responses in macrophages.
2015-03-31 | GSE66501 | GEO
Project description:Rett Syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5-7 days post-fertilization (dpf). We show that zebrafish mecp2 function is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2’s function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.
2024-01-01 | GSE252307 | GEO
Project description:Rett Syndrome (RTT) is a severe neurological disorder predominantly affecting females, caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. Understanding the pathophysiology of RTT at a cellular and molecular level is crucial for the development of targeted therapies. This project aims to dissect the molecular underpinnings of RTT using a novel in vitro model system based on a commercially available human neural progenitor cell line, ReNCell. We have engineered multiple distinct ReNCell lines to mimic specific genetic alterations associated with RTT, providing a robust platform for mechanistic studies and drug screening. One cell line is a complete knockout of MECP2, serving as a model to investigate the effects of total loss of MeCP2 function. This model helps in understanding the full spectrum of MeCP2's roles in neural development and maintenance, and in identifying compensatory mechanisms that could be targeted therapeutically. The other line involves the knockdown of NEAT1, a long non-coding RNA known to be involved in the pathogenesis of several neurological disorders, including RTT. Recent studies suggest NEAT1 plays a critical role in the neuronal cellular response to MECP2 dysfunction. By reducing NEAT1 expression, we aim to elucidate its contribution to RTT pathology and explore its potential as a therapeutic target. Here we characterize the transcriptome of these cell lines, including the wild type (control), at the progenitor state and after 7 days of differentiation with three replicates each.
2024-11-17 | E-MTAB-14048 | biostudies-arrayexpress