Ontology highlight
ABSTRACT:
PROVIDER: PRJNA950136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24011023.fastq.gz | Fastqsanger.gz | |||
| SRR24011023_1.fastq.gz | Fastqsanger.gz | |||
| SRR24011023_2.fastq.gz | Fastqsanger.gz | |||
| SRR24011024.fastq.gz | Fastqsanger.gz | |||
| SRR24011024_1.fastq.gz | Fastqsanger.gz |
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Project description:Over 400 million people worldwide are living with a rare disease, with genetic variants determining 80% of cases. Next Generation Sequencing identifies potential disease causative genetic variants, however many of these are classified as variants of uncertain significance (VUS). Each VUS requires functional validation as pathogenic or benign in disease pathology in specialist laboratories creating major delays in patient diagnosis. In this study we test a rapid genetic variant assessment pipeline using an EHMT1 (Euchromatin histone methyltransferase 1; EHMT1 p.Gln1144Ter) genetic variant that is pathogenic for Kleefstra Syndrome. Precise CRISPR homology directed (HDR) gene editing introduced the single nucleotide genetic variant in iPS cells and EHMT1_SNV cell clones were rapidly identified with amplicon sequencing. Induction of neural differentiation and RNA sequencing determined differences in differentiation at the gene and transcription factor level. The applied CRISPR HDR methodology was rapid and reliable for the introduction of SNVs in iPSCs for subsequent neuronal cell differentiation. Key features of Kleefstra Syndrome were identified, with involvement of key transcription factors REST and SP1 in disease mechanisms. This study indicates that precise iPSC gene editing and changes in disease modelling pathways can contribute to disease diagnosis and understanding of mechanisms.
2021-06-23 | GSE178646 | GEO
Project description:Nuclear deubiquitinase BAP1 (BRCA1-Associated Protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor gene whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a NDD or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder (NDD). Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired in matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
2021-12-10 | GSE190394 | GEO
Project description:Kleefstra syndrome 2 in an adult
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Project description:Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.
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Project description:Haploinsufficiency of the Euchromatin histone methyltransferase 1 (EHMT1) gene leads to Kleefstra Syndrome, a rare disease characterised by moderate to severe developmental delay/intellectual disability, childhood hypotonia and distinct facial features, comprising microcephaly. This study examines the genetic variant EHMT1_Ter (p.[Tyr1148=];[Tyr1148Leufs*9]) in HEK293 cells.
2020-09-04 | GSE157390 | GEO
Project description:KMT2C and KMT2D are two of the frequently mutated epigenetic modifiers in urothelial cancer. To compare the histone post-translational modification with Kmt2c/d loss, we performed mass spectrometry analysis of histones from Kmt2c/d WT and dKO urothelial cells.
2025-01-08 | PXD056439 | Pride
Project description:Mammalian genomes are replicated in a precise, cell-type-specific order during the S phase, a process that correlates with local transcriptional activity, chromatin modifications, and chromatin architecture. However, the causal relationships between these features and DNA replication timing (RT), particularly during cell fate transitions, remain largely unknown. Here, we employed machine learning to quantify chromatin features — including epigenetic marks, histone variants, and chromatin architectural factors — that best predict local RT under steady-state conditions and RT changes during early embryonic stem (ES) cell differentiation. We found that approximately one-third of the genome exhibits RT changes during differentiation. Chromatin features collectively predicted steady-state RT and RT changes with high accuracy. Notably, histone H3 lysine 4 monomethylation (H3K4me1), catalyzed by KMT2C/D, emerged as a top predictor. Genetic deletion of Kmt2c/d (but not Kmt2c alone) or their enzymatic activities erased genome-wide RT dynamics during cell differentiation. Sites that typically gain H3K4me1 in a KMT2C/D-dependent manner during differentiation failed to transition towards earlier RT, often without affecting transcriptional activation. Further analysis at KMT2C/D binding sites revealed a local requirement for KMT2C/D in promoting DNA replication origin firing. Our findings identify KMT2C/D-dependent H3K4me1 as a functional regulator of RT and origin firing, highlighting a causal relationship between the epigenome and DNA replication that is largely independent of transcription. These insights should be relevant to various diseases associated with KMT2C/D mutations. Mammalian genomes are replicated in a precise, cell-type-specific order during the S phase, a process that correlates with local transcriptional activity, chromatin modifications, and chromatin architecture. However, the causal relationships between these features and DNA replication timing (RT), particularly during cell fate transitions, remain largely unknown. Here, we employed machine learning to quantify chromatin features — including epigenetic marks, histone variants, and chromatin architectural factors — that best predict local RT under steady-state conditions and RT changes during early embryonic stem (ES) cell differentiation. We found that approximately one-third of the genome exhibits RT changes during differentiation. Chromatin features collectively predicted steady-state RT and RT changes with high accuracy. Notably, histone H3 lysine 4 monomethylation (H3K4me1), catalyzed by KMT2C/D, emerged as a top predictor. Genetic deletion of Kmt2c/d (but not Kmt2c alone) or their enzymatic activities erased genome-wide RT dynamics during cell differentiation. Sites that typically gain H3K4me1 in a KMT2C/D-dependent manner during differentiation failed to transition towards earlier RT, often without affecting transcriptional activation. Further analysis at KMT2C/D binding sites revealed a local requirement for KMT2C/D in promoting DNA replication origin firing. Our findings identify KMT2C/D-dependent H3K4me1 as a functional regulator of RT and origin firing, highlighting a causal relationship between the epigenome and DNA replication that is largely independent of transcription. These insights should be relevant to various diseases associated with KMT2C/D mutations.
2025-02-03 | GSE277790 | GEO
Project description:KMT2C is a frequently mutated gene in meningiomas, however, its functional role in meningioma pathogenesis remains poorly understood. Here we demonstrate that KMT2C expression is reduced in high-grade meningiomas and that its deficiency promotes tumor progression by inactivating the Hippo pathway. Mechanistically, KMT2C loss diminishes H3K27ac levels at transcription start sites (TSS) and disrupts chromatin accessibility, leading to transcriptional downregulation of NF2 and subsequent dysregulation of Hippo signaling. We further reveal that KMT2C deficiency impairs the acetyltransferase activity of CBP/EP300, thereby reducing H3K27ac deposition, while the chromatin binding of CBP/EP300 remains unaffected following KMT2C knockout. Treatment with the histone deacetylase inhibitor TSA restores H3K27ac levels and reactivates NF2 expression in KMT2C-deficient meningiomas. Notably, KMT2C loss sensitizes meningioma cells to ferroptosis, and the ferroptosis inducer erastin significantly suppresses tumor growth both in vitro and in vivo. These findings establish a foundation for developing targeted therapies for meningioma patients with KMT2C deficiency.
2025-12-12 | GSE312824 | GEO
Project description:Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders.
2020-09-14 | GSE120061 | GEO