KMT2D haploinsufficiency in Kabuki Syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation
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ABSTRACT:
PROVIDER: PRJEB46128 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6196250.fastq.gz | Fastqsanger.gz | |||
| ERR6196260.fastq.gz | Fastqsanger.gz | |||
| ERR6196270.fastq.gz | Fastqsanger.gz | |||
| ERR6196280.fastq.gz | Fastqsanger.gz | |||
| ERR6196290.fastq.gz | Fastqsanger.gz |
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Project description:Kabuki Syndrome (KS) is a multisystemic rare disorder, characterized by growth delay, distinctive facial features, intellectual disability, and rarely autism spectrum disorder. This condition is mostly caused by de novo mutations of KMT2D, encoding a catalytic subunit of the COMPASS complex involved in enhancer regulation. KMT2D catalyzes the deposition of histone-3-lysine-4 mono-methyl (H3K4Me1) that marks active and poised enhancers. To assess the impact of KMT2D mutations in the chromatin landscape of KS tissues, we have generated patient-derived induced pluripotent stem cells (iPSC), which we further differentiated into neural crest stem cells (NCSC), mesenchymal stem cells (MSC) and cortical neurons (iN). In addition, we further collected blood samples from 5 additional KS patients. To complete our disease modeling cohort we generated an isogenic KMT2D mutant line from human embryonic stem cells, which we differentiated into neural precursor and mature neurons. Micro-electrode-array (MEA)-based neural network analysis of KS iNs revealed an altered pattern of spontaneous network-bursts in a Kabuki-specific pattern. RNA-seq profiling was performed to relate this aberrant MEA pattern to transcriptional dysregulations, revealing that dysregulated genes were enriched for neuronal functions, such as ion channels, synapse activity, and electrophysiological activity. Here we show that KMT2D haploinsufficiency tends to heavily affect the transcriptome of cortical neurons and differentiated tissues while sparing multipotent states, suggesting that KMT2D has a most prevalent role in terminally differentiated cell and activate transcriptional circuitry unique to each cell type. Moreover, thorough profiling of H3K4Me1 unveiled the almost complete uncoupling between this chromatin mark and the regulatory effects of KMT2D on transcription, which is instead reflected by a defect of H3K27Ac. By integrating RNA-seq with ChIP-seq data we defined TEAD and REST as the master effectors of KMT2D haploinsufficiency. Also, we identified a subset of genes whose regulation is controlled by the balance between KMT2D and EZH2 dosage. Finally, we identified the bona fide direct targets of KMT2D in healthy and KS mature cortical neurons and TEAD2 as the main proxy of KMT2D dysregulation in KS. Overall, our study provides the transcriptional and epigenomic characterization of patient-derived tissues as well as iPSCs and differentiated disease-relevant cell types, as well as the identification of KMT2D direct target in cortical neurons, together with the identification of a neuronal phenotype of the spontaneous electrical activity.
2022-12-25 | E-MTAB-10244 | biostudies-arrayexpress
Project description:Kabuki Syndrome (KS) is a multisystemic rare disorder, characterized by growth delay, distinctive facial features, intellectual disability, and rarely autism spectrum disorder. This condition is mostly caused by de novo mutations of KMT2D, encoding a catalytic subunit of the COMPASS complex involved in enhancer regulation. KMT2D catalyzes the deposition of histone-3-lysine-4 mono-methyl (H3K4Me1) that marks active and poised enhancers. To assess the impact of KMT2D mutations in the chromatin landscape of KS tissues, we have generated patient-derived induced pluripotent stem cells (iPSC), which we further differentiated into neural crest stem cells (NCSC), mesenchymal stem cells (MSC) and cortical neurons (iN). In addition, we further collected blood samples from 5 additional KS patients. To complete our disease modeling cohort we generated an isogenic KMT2D mutant line from human embryonic stem cells, which we differentiated into neural precursor and mature neurons. Micro-electrode-array (MEA)-based neural network analysis of KS iNs revealed an altered pattern of spontaneous network-bursts in a Kabuki-specific pattern. RNA-seq profiling was performed to relate this aberrant MEA pattern to transcriptional dysregulations, revealing that dysregulated genes were enriched for neuronal functions, such as ion channels, synapse activity, and electrophysiological activity. Here we show that KMT2D haploinsufficiency tends to heavily affect the transcriptome of cortical neurons and differentiated tissues while sparing multipotent states, suggesting that KMT2D has a most prevalent role in terminally differentiated cell and activate transcriptional circuitry unique to each cell type. Moreover, thorough profiling of H3K4Me1 unveiled the almost complete uncoupling between this chromatin mark and the regulatory effects of KMT2D on transcription, which is instead reflected by a defect of H3K27Ac. By integrating RNA-seq with ChIP-seq data we defined TEAD and REST as the master effectors of KMT2D haploinsufficiency. Also, we identified a subset of genes whose regulation is controlled by the balance between KMT2D and EZH2 dosage. Finally, we identified the bona fide direct targets of KMT2D in healthy and KS mature cortical neurons and TEAD2 as the main proxy of KMT2D dysregulation in KS. Overall, our study provides the transcriptional and epigenomic characterization of patient-derived tissues as well as iPSCs and differentiated disease-relevant cell types, as well as the identification of KMT2D direct target in cortical neurons, together with the identification of a neuronal phenotype of the spontaneous electrical activity.
2024-06-30 | E-MTAB-10561 | biostudies-arrayexpress
Project description:The crosstalk between H3K4 monomethylation and DNA methylation has been receiving little attention to date. We investigated a mouse model harboring a loss-of-function mutation of lysine methyltransferase 2D (KMT2D), which catalyzes the monomethylation of lysine 4 on histone H3. We performed H3K4me1 ChIP-seq in spleen B cells with the wild type (WT) KMT2D as well as heterozygous (HET) and homozygous (HOM) chr15: 98,835,228 A>T KMT2D mutation. Alongside, using WGBS, we performed genome-wide DNA methylation profiling in spleen B cells with the WT KMT2D as well as HET and HOM chr15: 98,835,228 A>T KMT2D mutation.
2019-01-23 | GSE104781 | GEO
Project description:The crosstalk between H3K4 monomethylation and DNA methylation has been receiving little attention to date. We investigated a mouse model harboring a loss-of-function mutation of lysine methyltransferase 2D (KMT2D), which catalyzes the monomethylation of lysine 4 on histone H3. We performed H3K4me1 ChIP-seq in spleen B cells with the wild type (WT) KMT2D as well as heterozygous (HET) and homozygous (HOM) chr15: 98,835,228 A>T KMT2D mutation. Alongside, using WGBS, we performed genome-wide DNA methylation profiling in spleen B cells with the WT KMT2D as well as HET and HOM chr15: 98,835,228 A>T KMT2D mutation.
2019-01-23 | GSE104533 | GEO
Project description:10x v3 single cell RNA-Seq of cultured primary hippocampal neural stem/progenitor cells (NPCs) (isolated by microdissection from E17 day embryos) from wild type or Kmt2d+/B-Geo mice (a haploinsufficiency model of Kabuki Syndrome). Cells are either undifferentiated (day0) or differentiated via growth factor withdrawl for 2, 4, or 8 days.
2021-12-13 | GSE190514 | GEO
Project description:The crosstalk between H3K4 monomethylation and DNA methylation has been receiving little attention to date. We investigated DNA methylation profiles (using WGBS) of wild-type (WT) mouse ESCs, Mll3/Mll4 (Kmt2c/Kmt2d) mutant (dKO) ESCs and catalytic SET domain mutant (dCD) ESCs, which were kindly provided by the Wysocka Laboratory (Dorighi et al., 2017).
2019-01-23 | GSE118314 | GEO
Project description:Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. Our data reveals that lysine methyltransferase epigenetic regulation is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders.
2024-06-23 | PXD050547 | Pride
Project description:The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depends on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However how chromatin players contribute to the assembly of transcriptional condensates has not been addressed. By interrogating the effect of KMT2D haploinsufficiency in Kabuki Syndrome, we found that MLL4 contributes in the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss-of-function impaired Polycomb-dependent chromatin compartmentalization, altering nuclear architecture. By releasing the nuclear mechanical stress through the inhibition of the mechano-sensor ATR, we re-established the mechano-signaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that in Kabuki Syndrome the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.
2020-09-22 | PXD021616 | Pride
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