Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism

ABSTRACT: Autism affects males four times more often than females, yet the basis of this sex bias remains unclear. One hypothesis is that hypomorphic variants in X-linked genes—genes where loss-of-function alleles cause syndromic neurodevelopmental disorders (NDDs) predominantly in females—produce milder, non-syndromic phenotypes in hemizygous males. We tested this by investigating cis-regulatory elements (CREs) of MECP2, a dosage-sensitive X-linked gene. Using a massively parallel reporter assay in human neurons, we mapped transcription factor binding sites within MECP2 CREs and tested autism-associated variants for functional impact. We identified two noncoding variants that change CRE activity, each with a male-biased phenotype. One of these, a promoter variant, disrupts NFY binding and reduces MECP2 expression by ~30%, a magnitude that produces autism-like phenotypes in mice. These findings suggest noncoding MECP2 variants can cause non-syndromic, male-biased autism, and provide a framework for uncovering regulatory variants in other X-linked NDD genes that may contribute to autism’s missing heritability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330364 | GEO | 2026/05/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase KDM5C

Project description:Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with un-known mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine de-methylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we re-port that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific con-sequences of a reduced KDM5C dose in social behavior, gene expression, and ge-netic interaction with the counteracting enzyme KMT2A. These observations pro-vide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.

2023-02-15 | GSE206346 | GEO

Transcription profiling of human super frontal gyrus (post mortem brain) from Rett syndrome patients and age sex matched controls reveals FXYD1, an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice

Project description:Rett syndrome (RTT, OMIM 312750) is a severe X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. The disorder is almost exclusively diagnosed in females, because males affected by the disease usually die perinatally due to severe encephalopathy. Direct MeCP2 target genes underlying the neuropathogenesis of RTT remain largely unknown.

2007-11-02 | E-GEOD-6955 | biostudies-arrayexpress

Differential infection tolerance mediates sex-biased illness severity in sepsis

Project description:Sepsis impacts males and females differently. Males have higher incidence, illness severity and mortality in sepsis than females. In this study, we use mouse models of fecal-induced peritonitis (FIP) to study sex disparities in sepsis. Male mice show higher illness severity, physiological derangement and end-organ dysfunction compared to females. Sex-biased outcome was driven by gonadal sex but not chromosome-linked gene effects. The results of this study indicate that male-biased sepsis severity is driven by impaired infection tolerance in males due to sex-biased mechanisms of mitochondrial function. We did not find differences in infection resistance or canonical immune/inflammatory pathways between males and female mice. Here we performed RNA-sequencing on mouse liver hepatocytes of uninfected and septic males and females.

2025-07-28 | GSE303231 | GEO

Complete dosage compensation and sex-biased gene expression in Manduca sexta

Project description:Using 4 replicate males and 4 replicate females this experiment examined dosage compensation and sex-biased gene expression. Briefly we performed a de novo assembly of the Manduca sexta transcriptome using all sequenced libraries, quantified genes expression, identified the physical locations of genes through orthology to the moth Bombyx mori and examine expression differences between autosomal and Z-linked genes between males and females. Further, we examined sex-biased gene expression using the replicated data.

2014-03-18 | E-MTAB-2066 | biostudies-arrayexpress

Single-nucleus profiling reveals a core disease signature and cell-type-specific vulnerabilities in early Rett syndrome

Project description:Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations. Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have ~50% of cells expressing either a mutant or wild-type copy of MECP2 (mosaic) and males have 100% of cells expressing a mutant MECP2 (non-mosaic). Typical RTT females have a short window of normal early development until ~6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males. How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female (Mecp2+/-) and male (Mecp2-/y) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice. We identified a core disease signature consisting of 12 genes consistently dysregulated only in MeCP2- cells across RTT models. Moreover, we uncovered non-cell-autonomous effects exclusively in female MeCP2+ excitatory neurons, but not inhibitory neurons, suggesting excitatory circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed that a previously underappreciated MeCP2- interneuron subtype had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and non-mosaic environment that appear early in RTT pathogenesis.

2026-05-06 | GSE301254 | GEO

Transcriptomic Analysis of the Hippocampus from Six Inbred Strains of Mice Suggests Basis for Sex-Specific Susceptibility and Severity of Neurological Disorders

Project description:Identifying sex differences in gene expression within the brain is critical for determining why multiple neurological and behavioural disorders differentially affect males and females. Several are more common or severe in males (e.g., autism and schizophrenia) or females (e.g., Alzheimerâs disease and depression). We analyzed transcriptomic data from the mouse hippocampus of six inbred strains (129S1/SvImJ, A/J, C57BL/6J, DBA/1J, DBA/2J and PWD/Ph), to provide a perspective on differences between male and female gene expression. Our data show that: 1) significant gene expression differences in males versus females varies substantially across the strains, 2) 12 genes exist that are differentially expressed across the inbred strains (termed core genes), and 3) there are >2,600 significantly differentially expressed genes (DEGs) among the strains (termed non-core genes). We found that DBA/2J uniquely has a substantial majority (89%) of DEGs that are more highly expressed in females than males; 129/SvImJ is the most strongly male-biased with a majority (69%) of DEGs that are more highly expressed in males. To gain insight into the sex-biased DEGs, we examined gene ontology, pathway and phenotype enrichment and found significant enrichment in phenotypes related to abnormal nervous system morphology and physiology, among others. In addition, several pathways are enriched significantly, including Alzheimerâs disease (AD), with 32 genes implicated in AD, 8 of which are male-biased. Three of the male-biased genes have been implicated in a neuroprotective role in AD. Our transcriptomic data provide new insight into understanding the possible genetic bases for sex-specific susceptibility and severity of brain disorders. Hippocampal mRNA from adult males and females of six inbred strains of mice were analyzed by RNA sequencing of 3 biological replicates using an Illumina HiSeq 2500

2016-01-06 | E-GEOD-76567 | biostudies-arrayexpress

Comparative Phosphoproteomic Profiling of Type III Adenylyl Cyclase Knockout and Control, Male and Female Mice Prefrontal Cortex

Project description:Type III adenylyl cyclase (AC3, ADCY3) is predominantly enriched in neuronal primary cilia throughout the central nervous system (CNS). Genome-wide association studies in humans have associated ADCY3 with major depressive disorder and autistic spectrum disorder, both of which exhibit sexual dimorphism. To date, it is unclear how AC3 affects protein phosphorylation and signal networks in central neurons, and what causes the sexual dimorphism of autism. We employed a mass spectrometry (MS)-based phosphoproteomic approach to quantitatively profile differences in phosphorylation between inducible AC3 knockout (KO) and wild type (WT), male and female mice. In total, we identified 4655 phosphopeptides from 1756 proteins, among which 565 phosphopeptides from 322 proteins were repetitively detected in all samples. Comparison of AC3 KO and WT datasets revealed that phosphopeptides with motifs matching proline-directed kinases’ recognition sites had a lower abundance in the KO dataset than in WTs. We detected 14 phosphopeptides restricted to WT dataset (i.e., from Spast and Ppp1r14a) and 35 exclusively in KOs (i.e., from Sptan1, Arhgap20, Arhgap44, and Pde1b). Moreover, 95 phosphopeptides were identified only in female dataset and 26 only in males. Label-free MS spectrum quantification using Skyline further identified phosphopeptides that had high expression abundance in each sample group. In total, over 200 modifications were gender-biased and had increased expression in females relative to males. 29% gender-biased phosphopeptides were from autism-associated proteins, including Dlg1, Dlg4, Dlgap2, Syn1, Syngap1, Ctnna1, Ctnnd1, Ctnnd2, Pkp4, and Arvcf. These autism proteins were well-connected in protein-protein interaction network that centered around Dlg4. This study provided the first phosphoproteomics evidence, suggesting that gender-biased post-translational phosphorylation may be implicated in the sexual dimorphism of autism.

2019-04-10 | PXD012259 | Pride

Xi-reactivation: A mixed modality approach to MECP2 restoration for Rett Syndrome and other X-linked disorders

Project description:The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset — including neurodevelopmental disorders, Rett, Fragile X, and CDKL5 Syndromes — also affects females. These disorders lack disease-specific treatment. Because female cells carry two X-chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here we focus on MECP2 restoration for Rett Syndrome and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X-inactivation. We identify a mixed modality approach combining an Xist antisense oligonucleotide and a small molecule inhibitor of DNA methylation, which together achieve 30,000-fold MECP2 upregulation from the Xi in cultured cells. Combining a brain-specific genetic Xist ablation with short-term Aza treatment models the synergy in vivo without evident toxicity. The Xi is selectively reactivated. These experiments provide proof of concept for a mixed modality approach for treating X-linked disorders in females.

2018-01-04 | GSE97077 | GEO

Identification of conserved cis-regulatory elements impact Mecp2 level and neurological functions

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

Variants in ZFX Cause an X-linked Neurodevelopmental Disorder with Recurrent Facial Gestalt

Project description:Pathogenic variants in multiple X-linked genes have been implicated in syndromic and non- syndromic intellectual disability disorders. The gene ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not previously been reported in association with disease. Here, we present clinical and molecular characterization of 18 patients with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven frameshift variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum and ear abnormalities. Hyperparathyroidism was found in 4 families with missense variants and enrichment of different types of tumors was also observed. In molecular studies, variants in the DNA-binding domain demonstrated differential expression of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, supporting the pathogenicity of predicted loss- of-function frameshift variants. Our clinical and experimental data support that variants in ZFX cause a novel X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

2023-11-30 | GSE218688 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data