The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression
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ABSTRACT:
PROVIDER: PRJNA435414 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6760410_1.fastq.gz | Fastqsanger.gz | |||
| SRR6760410_2.fastq.gz | Fastqsanger.gz | |||
| SRR6760420.fastq.gz | Fastqsanger.gz | |||
| SRR6760411_1.fastq.gz | Fastqsanger.gz | |||
| SRR6760411_2.fastq.gz | Fastqsanger.gz |
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Project description:Myoblast fusion (MF) is a complex process required for muscle formation. During development, post-natal muscle growth and adult muscle regeneration, myoblasts proliferate and fuse to generate multinucleated fibers. MF defects have been described in an increasing number of muscle diseases. Moreover, MF plays also a relevant role in the delivery of therapeutics to muscle fibers. Hence, the identification of novel MF activators bears strong therapeutic relevance. Despite the central role of MF, the mechanisms governing this process are incompletely understood, and no epigenetic regulator has ever been described. Ash1L is a histone methyltransferase responsible for H3K36me2 and a member of the Trithorax group of epigenetic activators. It is involved in several diseases, including FSHD muscular dystrophy, autism and cancer. Nevertheless, its physiological role in skeletal muscle is unknown. For the first time, we found that Ash1L expression is regulated during skeletal muscle development, positively correlated with that of key MF genes and reduced in Duchenne muscular dystrophy. During physiological muscle differentiation or muscle regeneration, Ash1L shows a peak of expression coincident with the activation of MF. Loss-of-function experiments support a selective and evolutionary conserved requirement for Ash1L in MF. Accordingly, Ash1L KO mice display small and underdeveloped skeletal muscles due to a MF defect. By combining RNA- and ChIP-sequencing, we identified direct Ash1L targets in muscle. Intriguingly, nearly all of them are known Polycomb target genes suggesting that Ash1L is required to counteract Polycomb repressive activity to allow activation of key myogenesis genes. In particular, we found that Ash1L drives MF by directly activating the expression of the key MF gene Cdon. Our results promote Ash1L as the first epigenetic regulator of MF and suggest that its activity could be targeted to improve cell therapy for muscle diseases.
2018-10-02 | GSE110957 | GEO
Project description:Myoblast fusion (MF) is required for muscle growth and repair, and its alteration contributes to muscle diseases. The mechanisms governing this process are incompletely understood, and no epigenetic regulator has been previously described. Ash1L is an epigenetic activator belonging to the Trithorax group of proteins and is involved in FSHD muscular dystrophy, autism and cancer. Its physiological role in skeletal muscle is unknown. Here we report that Ash1L expression is positively correlated with MF and reduced in Duchenne muscular dystrophy. In vivo, ex vivo and in vitro experiments support a selective and evolutionary conserved requirement for Ash1L in MF. RNA- and ChIP-sequencing indicate that Ash1L is required to counteract Polycomb repressive activity to allow activation of selected myogenesis genes, in particular the key MF gene Cdon. Our results promote Ash1L as an important epigenetic regulator of MF and suggest that its activity could be targeted to improve cell therapy for muscle diseases.
| S-EPMC6262021 | biostudies-literature
Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention. Investigation of multiple transcription factors and histone modification marks in MV4-11 human leukemia cells.
2016-07-01 | E-GEOD-73528 | biostudies-arrayexpress
Project description:Myoblast fusion is fundamental for the development of multinucleated myofibers. Evolutionarily conserved proteins required for myoblast fusion include Rac1 and its activator Dock1. Here, we tested the functions of Elmo proteins, Dock1-interacting scaffolds, on myoblast fusion. When Elmo1-/- mice underwent muscle-specific Elmo2 genetic ablation, they exhibited severe myoblast fusion defects. A mutation in the Elmo2 gene that reduced signaling resulted in a decrease in myoblast fusion. Conversely, a mutation in Elmo2 promoting its open conformation increased myoblast fusion during development and in muscle regeneration. Finally, we showed that the dystrophic features of the Dysferlin-null mice, a model of limb-girdle muscular dystrophy type 2B, were reversed when expressing Elmo2 in an open conformation. These data provide direct evidence that the myoblast fusion process could be exploited for regenerative and therapeutic purposes.
2022-07-25 | GSE209546 | GEO
Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention.
2016-07-01 | GSE73528 | GEO
Project description:The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes that they regulate remain poorly defined. Here we find that activity of p38α/β is important not only for early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treating C2 myoblasts with the pro-myogenic growth factor, IGF-I, we were able to overcome the early block in differentiation imposed by co-incubation with the p38 chemical inhibitor, SB202190. Yet, IGF-I could not overcome the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts showed that the fusion block was reversible, as multinucleated myofibers were detected several hours later, and reached ~90% of the culture within 30 hours. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of up-regulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion, which should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis.
2018-10-24 | PXD002413 | Pride
Project description:Ash1l encodes a histone methyltransferase, a member of the trithorax group proteins, which regulates developmental essential gene expression by catalyzing H3K36 methylation and counteracting polycomb silencing. Accumulating reports suggest the loss-of-function mutants in Ash1l gene are associated with intellectual disability (ID), attention-deficit/hyperactivity (ADHD), autism spectrum disorder (ASD), Tourette syndrome (TS) and multiple congenital anomalies (MCA). We performed transcriptional profiling of dorsal striatum in 1-year-old Ash1l mutant brain via RNA sequencing (RNA-seq). Ash1l haploinsufficiency induces transcription alternation of genes involved in synaptic function and cortical development, implicating the deficits in synapse pruning and behavior in adult mice.
2022-01-25 | GSE173502 | GEO
Project description:Ash1l encodes a histone methyltransferase, a member of the trithorax group proteins, which regulates developmental essential gene expression by catalyzing H3K36 methylation and counteracting polycomb silencing. Accumulating reports suggest the loss-of-function mutants in Ash1l gene are associated with intellectual disability (ID), attention-deficit/hyperactivity (ADHD), autism spectrum disorder (ASD), Tourette syndrome (TS) and multiple congenital anomalies (MCA). We performed transcriptome analysis of auditory cortex in 1-month-old and 1-year-old Ash1l Ash1l heterozygous mice with their age-matched WT littermates via RNA sequencing (RNA-seq). Ash1l haploinsufficiency induces transcription alternation of genes involved in synaptic function and cortical development, implicating the deficits in synapse pruning and behavior in adult mice.
2022-01-25 | GSE184375 | GEO
Project description:Cells dynamically change their internal organization via continuous cell state transitions to mediate a plethora of physiological processes. Understanding such continuous processes is severely limited due to a lack of tools to measure the holistic physiological state of single cells undergoing a transition. We combined live-cell imaging and machine learning to quantitatively monitor skeletal muscle precursor cell (myoblast) differentiation during multinucleated muscle fiber formation. Our machine learning model predicted the continuous differentiation state of single primary murine myoblasts over time and revealed that inhibiting ERK1/2 leads to a gradual transition from an undifferentiated to a terminally differentiated state 7.5-14.5 hours post inhibition. Myoblast fusion occurred ~3 hours after predicted terminal differentiation. Moreover, we showed that our model could predict that cells have reached terminal differentiation under conditions where fusion was stalled, demonstrating potential applications in screening. This method can be adapted to other biological processes to reveal connections between the dynamic single-cell state and virtually any other functional readout.
2024-05-23 | PXD047198 | Pride
Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.
2021-09-07 | GSE183413 | GEO