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Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

ABSTRACT: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

PROVIDER: PRJNA562716 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10031201.fastq.gz	Fastqsanger.gz
	SRR10031202.fastq.gz	Fastqsanger.gz
	SRR10031203.fastq.gz	Fastqsanger.gz
	SRR10031204.fastq.gz	Fastqsanger.gz
	SRR10031205.fastq.gz	Fastqsanger.gz

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Similar Datasets

DamID: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

Project description:DamID: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

| PRJNA560279 | ENA

RNA-seq: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

Project description:RNA-seq: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

| PRJNA562715 | ENA

RNA-seq: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

Project description:Point mutations in nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery Dreifuss Muscular Dystrophy (EDMD)-inducing mutation (lamin A-Y45C) into C. elegans lamin (LMN-Y59C), recapitulates many EDMD phenotypes, and correlates with hyper-sequestration of heterochromatic arrays at the nuclear periphery. Using muscle-specific emerin Dam-ID, we also document the misorganization of endogenous chromatin in the LMN-Y59C mutant. We score increased perinuclear positioning along chromosome arms, and enhanced release within chromosomal cores. Coincidentally, Y59C worms have reduced locomotion and compromised sarcomere integrity. By coupling the Y59C mutation with deletion of the perinuclear chromodomain protein CEC-4, which tethers H3K9-methylated chromatin, we rescue the EDMD-like physiology and ultrastructural defects in sarcomeres. Deletion of cec-4 also rescued the Y59C-induced changes in chromatin organization. The promoters of genes that change position in the LMN-Y59C mutant, are enriched for E2F (EFL-1/-2) binding sites, consistent with previous studies implicating the Rb-E2F interaction with lamin A in muscle dysfunction. Gene expression changes provoked by LMN-Y59C are also largely reversed by cec-4 deletion. In summary, the ablation of a perinuclear H3K9me-anchor can counteract the dominant muscle-specific defects provoked by a laminopathic mutation, implicating peripheral chromatin organization in the control of muscle integrity.

2020-12-31 | GSE136576 | GEO

DamID: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

Project description:Point mutations in nuclear structural protein laminA produce rare and generally tissue-specific diseases called laminopathies. The introduction of a human Emery Dreifuss Muscular Dystrophy (EDMD)-inducing mutation (laminA-Y45C) into C. elegans lamin (LMN-Y59C), recapitulates many EDMD phenotypes, and results in hyper-sequestration of heterochromatic arrays at the nuclear periphery. Using muscle-specific Emerin Dam-ID we show that the LMN-Y59C mutation also leads to misorganization of endogenous chromatin. We find increased perinuclear anchoring primarily along chromosome arms, and enhanced release of chromosomal cores. Coincidentally, Y59C worms have reduced locomotion and compromised sarcomere integrity. By coupling this mutation with deletion of the perinuclear chromodomain protein CEC-4, which tethers H3K9-methylated chromatin, we rescue the EDMD-like physiology and ultrastructural defects in sarcomeres. It further counteracts the altered spatial organization of chromosomal sequences, particularly along chromosomal arms. The data in this submission refer to the identification of chromatin enriched at the nuclear periphery (as measured by interaction with Dam::EMR-1) in muscle cells of L3/L4 control animals or cec-4 mutants expressing either GFP::LMN-1 (wild type lamin) or GFP::LMN-1(Y59C).

2020-12-31 | GSE135850 | GEO

Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-31 | GSE136577 | GEO

Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts.

Project description:LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level-at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients. Since other laminopathies also result in production of abnormal and potentially toxic lamin proteins, we hypothesized that everolimus would also be beneficial in those disorders. To test this, we applied everolimus to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA Everolimus treatment increased proliferative ability and delayed senescence in all cell lines. In several cell lines, we observed that with treatment, there is a significant improvement in nuclear blebbing, which is a cellular hallmark of HGPS and other lamin disorders. These preclinical results suggest that everolimus might have clinical benefit for multiple laminopathy syndromes.

| S-EPMC5910873 | biostudies-literature

Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model.

Project description:Mutations in the nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery-Dreifuss muscular dystrophy (EDMD)-inducing mutation into the C. elegans lamin (LMN-Y59C), recapitulates many muscular dystrophy phenotypes, and correlates with hyper-sequestration of a heterochromatic array at the nuclear periphery in muscle cells. Using muscle-specific emerin Dam-ID in worms, we monitored the effects of the mutation on endogenous chromatin. An increased contact with the nuclear periphery along chromosome arms, and an enhanced release of chromosomal centers, coincided with the disease phenotypes of reduced locomotion and compromised sarcomere integrity. The coupling of the LMN-Y59C mutation with the ablation of CEC-4, a chromodomain protein that anchors H3K9-methylated chromatin at the nuclear envelope (NE), suppressed the muscle-associated disease phenotypes. Deletion of cec-4 also rescued LMN-Y59C-linked alterations in chromatin organization and some changes in transcription. Sequences that changed position in the LMN-Y59C mutant, are enriched for E2F (EFL-2)-binding sites, consistent with previous studies suggesting that altered Rb-E2F interaction with lamin A may contribute to muscle dysfunction. In summary, we were able to counteract the dominant muscle-specific defects provoked by LMNA mutation by the ablation of a lamin-associated H3K9me anchor, suggesting a novel therapeutic pathway for EDMD.

| S-EPMC7111258 | biostudies-literature

The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis. [Expression Profile]

Project description:Histone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1M-bM-^@M-^SMLL4) whose specific functions are largely unknown. By using a genomic approach, we found that in macrophages, MLL4 (also known as Wbp7) was required for the expression of Pigp, an essential component of the GPI-GlcNAc transferase, the enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor synthesis. Impaired Pigp expression in Wbp7-/- macrophages abolished GPI anchor-dependent loading of proteins on the cell membrane. Consistently, loss of GPI-anchored CD14, the coreceptor for lipopolysaccharide (LPS) and other bacterial molecules, markedly attenuated LPS-triggered intracellular signals and gene expression changes. These data link a histone-modifying enzyme to a biosynthetic pathway and indicate a specialized biological role for Wbp7 in macrophage function and antimicrobial response. Gene expression profiles for bone marrow-derived macrophages (BMDM) from either Wbp7+/- (HET) or Wbp7-/- (KO). Cells were left untreated or challenged with lipopolysaccharide (LPS) for 2hrs or 4hrs. Each genotype-treatment combination were performed in triplicate.

2012-04-08 | E-GEOD-30971 | biostudies-arrayexpress

The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis. [ChIP_seq]

Project description:Histone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1M-bM-^@M-^SMLL4) whose specific functions are largely unknown. By using a genomic approach, we found that in macrophages, MLL4 (also known as Wbp7) was required for the expression of Pigp, an essential component of the GPI-GlcNAc transferase, the enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor synthesis. Impaired Pigp expression in Wbp7-/- macrophages abolished GPI anchor-dependent loading of proteins on the cell membrane. Consistently, loss of GPI-anchored CD14, the coreceptor for lipopolysaccharide (LPS) and other bacterial molecules, markedly attenuated LPS-triggered intracellular signals and gene expression changes. These data link a histone-modifying enzyme to a biosynthetic pathway and indicate a specialized biological role for Wbp7 in macrophage function and antimicrobial response. Chromatin immuno-precipitations of H3 histone try-methylated on lysine 4 followed by multiparallel sequencing performed in murine bone marrow-derive macrophages (BMDM). Experiments carried out in untreated cells as well as in cells treated for 4hrs with lipopolysaccharide (LPS), for both Wbp7+/- (HET) and Wbp7-/- (KO) mice.

2012-04-09 | E-GEOD-30972 | biostudies-arrayexpress

The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis

Project description:This SuperSeries is composed of the following subset Series: GSE30971: The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis. [Expression Profile] GSE30972: The Histone Methyltransferase Wbp7 Controls Macrophage Function through GPI Glycolipid Anchor Synthesis. [ChIP_seq] Refer to individual Series

2012-04-08 | E-GEOD-30973 | biostudies-arrayexpress

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