DMD-TGFb-SETDB1
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ABSTRACT:
PROVIDER: PRJEB63300 | ENA |
REPOSITORIES: ENA
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Project description:Duchenne Muscular Dystrophy (DMD) is a severe X-linked muscle-wasting disorder characterized by chronic inflammation, progressive fibrosis, and impaired muscle regeneration. The TGFb pathway is overactivated in DMD and it sustains the accumulation of extracellular matrix (ECM), contributing to fibrosis. Our previous results showed that SETDB1 regulates the expression of TGFb-dependent secreted factors impacting fibrosis and myogenic differentiation. In particular, the conditioned medium (CM) of TGFb-treated myotubes impairs myoblasts differentiation and increase fibrosis. In this study, we performed a thorough proteomic analysis of the secretome from DMD myotubes under TGFb stimulation, with or without SETDB1 LOF, to identify secreted factors involved in the dysregulated regenerative environment of DMD. We found that SETDB1 modulates the TGFb-induced secretome, particularly by regulating ECM-related proteins. Among these, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle. EMILIN1 is upregulated by TGFb reduced upon SETDB1 depletion and more abundant in DMD myotubes. Functional analyses revealed that EMILIN1 LOF impairs late myogenic differentiation and reduces the expression of the fibrotic marker SERPINE1. These findings highlight EMILIN1 as a secreted regulator of myogenesis and fibrosis, and support the role of SETDB1 in regulating the TGFb-dependent secretome in DMD. This study provides new insights into the molecular players contributing to the fibrotic and regenerative defects in DMD, offering potential therapeutic targets for disease intervention.
2026-08-24 | PXD068544 | Pride
Project description:Duchenne Muscular Dystrophy (DMD) is an incurable muscle-wasting disorder characterized by chronic membrane damage, inflammation, and progressive fibrosis. Fibrosis in DMD is driven by sustained TGF signaling, which promotes extracellular matrix (ECM) accumulation. We previously showed that SETDB1 sustains the TGF-induced fibrotic response in DMD myotubes. Here, we further show that SETDB1 modulates the TGF-induced secretome, particularly by regulating ECM-related proteins. Comparison of the basal secretome from DMD patient-derived myotubes and healthy controls revealed a distinct disease-specific profile. Integrating both secretome analyses, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle, as a robust shared candidate; EMILIN1 is enriched in the DMD secretome, further upregulated by TGF and downregulated upon SETDB1 depletion. We confirmed EMILIN1 overexpression in DMD patient muscle biopsies, validating its pathological relevance. Functionally, EMILIN1 depletion modulated myogenic differentiation and reduced expression of the fibrotic marker SERPINE1. These findings establish EMILIN1 as a novel secreted regulator of myogenesis and fibrosis, and implicate SETDB1 in shaping the TGF-dependent secretome in DMD. Our integrative proteomic approach provides new insights into the molecular drivers of impaired regeneration in DMD and highlights potential therapeutic targets.
2026-08-24 | PXD074360 | Pride
Project description:The Dystrophin gene (DMD) is the largest gene in the human genome, mapping on Xp21, spanning 2.2Mb and accounting for approximately 1% of the entire human genome. Mutations in this gene cause Duchenne and Becker muscular dystrophy, X-linked dilated cardiomyopathy, and other milder muscle phenotypes. Beside the remarkable number of reports describing dystrophin gene expression and the pathogenic consequences of the gene mutations in dystrophinopathies, the full scenario of the DMD transcription dynamics remains however, poorly understood. Considering that the full transcription of the DMD gene requires about 16 hours, we have investigated the activity of RNA Polymerase II along the entire DMD locus within the context of specific chromatin modifications using a variety of chromatin-based techniques. Our results unveil a surprisingly powerful processivity of the RNA pol II along the entire 2.2 Mb of the DMD locus with just one site of pausing around intron 52. More importantly, epigenetic marks highlighted the existence of four novel cis-DNA elements, two of which, located within intron 34 and exon 45, appear to govern the architecture of the DMD chromatin with implications on the expression levels of the muscle dystrophin mRNA. Overall, our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies.
2018-03-01 | GSE66571 | GEO
Project description:The histone 3 lysine 9 (H3K9)-specific methyltransferase (KMT) Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on Setdb1 role(s) in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies on isolated single myofibres showed that Setdb1 is required for muscle adult stem cells expansion following activation and in vitro studies on skeletal myoblasts confirmed that Setdb1 suppresses terminal myoblast differentiation. We used genome-wide analyses to identify Setdb1 direct target genes in myoblasts and observed a release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation, concomitant to a nuclear export of Setdb1 to the cytoplasm. We demonstrated that both genomic release and cytoplasmic Setdb1 relocalisation during differentiation were dependent on canonical Wnt signalling. Taken together, our findings uncover a functional link between Setdb1 and canonical Wnt signalling in skeletal muscle cells, which affects the expression of a subset of Setdb1 target genes. We revealed Wnt-dependent subcellular relocalisation of Setdb1 as a novel mechanism regulating Setdb1 functions. ChIP-seq of Setdb1 and H3K9me3 in Myoblast cells (C2C12)
2016-02-01 | E-GEOD-65493 | biostudies-arrayexpress
Project description:Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins (PHD) and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element (TE)-derived double-stranded RNAs (dsRNAs), thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.
2024-01-26 | PXD037104 | Pride
Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells and characterized genome-wide SetDB1 binding and H3K9 trimethylation (H3K9me3) profiles in mouse ES cells and uncovered two distinct classes of SetDB1 binding sites, termed solo and ensemble peaks. The solo peaks were devoid of H3K9me3 and enriched near developmental regulators while the ensemble peaks were associated with H3K9me3. A subset of the SetDB1 solo peaks, particularly those near neural development related genes, was found to be associated with Polycomb Repressive Complex 2 (PRC2) as well as PRC2-interacting proteins Jarid2 and Mtf2. Genetic deletion of Setdb1 dramatically reduced Ezh2 binding as well as histone 3 lysine 27 (H3K27) trimethylation level at SetDB1 solo peaks and facilitated neural differentiation. Furthermore, we found that H3K27me3 inhibits SetDB1 methyltransferase activity in vitro. The currently identified reciprocal action between SetDB1 and PRC2 reveals a novel mechanism underlying ES cell pluripotency and differentiation regulation. Examination of 2 different histone modifications in 2 cell status.
2015-06-25 | E-GEOD-62666 | biostudies-arrayexpress
Project description:Only a small percentage of human transcription factors (e.g. those associated with a specific differentiation program) are expressed in a given cell type. Thus, cell fate is mainly determined by cell type-specific silencing of transcription factors that drive different cellular lineages. Several histone modifications have been associated with gene silencing, including H3K27me3 and H3K9me3. We have previously shown that the two largest classes of mammalian transcription factors are marked by distinct histone modifications; homeobox genes are marked by H3K27me3 and zinc finger genes are marked by H3K9me3. Several histone methyltransferases (e.g. G9a and SETDB1) may be involved in mediating the H3K9me3 silencing mark. We have used ChIP-chip (GSE24480) and ChIP-seq to demonstrate that SETDB1, but not G9a, is associated with regions of the genome enriched for H3K9me3. A current model is that SETDB1 is recruited to specific genomic locations via interaction with the corepressor TRIM28 (KAP1), which is in turn recruited to the genome via interaction with zinc finger transcription factors that contain a Kruppel-associated box (KRAB) domain. However, specific KRAB-ZNFs that recruit TRIM28 (KAP1) and SETDB1 to the genome have not been identified. We now show that ZNF274 (a KRAB-ZNF that contains 5 C2H2 zinc finger domains), can interact with KAP1 in vitro and, using ChIP-seq, we show that ZNF274 binding sites co-localize with SETDB1, KAP1, and H3K9me3 at the 3’ ends of zinc finger genes. Knockdown of ZNF274 with siRNAs reduced the levels of KAP1 and SETDB1 recruitment to the binding sites. These studies provide the first identification of a KRAB domain-containing ZNFs that is involved in recruitment of the KAP1 and SETDB1 to the human genome. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf 7 total ChIP-seq datasets; 4 ZNF274 datasets done in duplicate from 4 different cell lines; 1 KAP1 duplicate dataset done in duplicate from K562 cells; 1 SetDB1 duplicate dataset from K562 cells; 1 H3K9me3 duplicate dataset from K562 cells
2010-11-15 | E-GEOD-24632 | biostudies-arrayexpress
Project description:Primairy human myoblast cell cultures Healthy DMD
2010-06-09 | E-GEOD-2693 | biostudies-arrayexpress
Project description:Comparative effects of Duchenne Muscular Dystrophy (DMD) and Aging in skeletal muscle Expression profiling established by microarray technology provides a powerful tool by which complex pathways can be assembled. The pathophysiology of Duchenne Muscular Dystrophy (DMD) is a complex process involving many pathways downstream of the primary genetic insult (lack of dystrophin). Similarly, the mechanisms implicated in muscle aging are only partially understood. The objective of the present study was to compare the muscle transcriptional response downstream of lack of dystrophin with the molecular events associated with aging using a muscle-dedicated microarray. Defining a common transcriptional profile in a range of wasting diseases should increase our understanding of the critical adaptations associated with muscle atrophy independent of the cause of the muscle wasting. RNA samples from 4 DMD and 4 AGE skeletal muscle tissues were analyzed by hybridization against control samples. This hybridization was done on microarrays containing quadruplicate 50-mer oligonucleotides corresponding to 3,588 muscle relevant genes. Two hybridizations were per-formed for each subject. Thus, eight values per gene were obtained for each subject. These stringent conditions conferred powerful significance to our results.
2011-11-01 | E-GEOD-32720 | biostudies-arrayexpress
Project description:Primairy human myoblast cell cultures Healthy DMD Keywords: time-course
2005-11-15 | GSE2693 | GEO