Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

Khilji, Saadia; Hamed, Munerah; Chen, Jihong; Li, Qiao

doi:10.1080/15592294.2018.1489659

Cited by 16 publications

(21 citation statements)

References 63 publications

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“…Interestingly, we have found that p300 is mainly associated with active promoters in response to RXR signaling ( Fig. 4), contrasting to its large association to enhancers in the absence of rexinoids 12 . Also, p300 may be recruited to the promoters by Atf1, Sp1 and bZIP binding proteins, where Atf1 motif displayed the largest enrichment at p300 associated promoters unique to rexinoid (Fig.…”

Section: Discussionmentioning

confidence: 79%

“…Genome-wide profiling of histone marks has allowed segmentation of the myoblast genome into distinct chromatin states characterized by a combination of histone modification patterns present in those regions 10 . During myoblast differentiation, an overall decrease in acetylation of H3K9, H3K18, and H3K27 11,12 is accompanied by an increase in H4 acetylation, specifically at MyoD targets 8,12 . Overexpression of myogenin in differentiating C2C12 myoblasts correlates to hyperacetylation of H4, which is associated specifically to late muscle genes 13 .…”

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confidence: 99%

“…In contrast, H3K27me3 is tightly associated with inactive genes and has a predictive nature of gene silencing 27 . We have recently utilized different histone marks within the proliferating myoblasts to generate a 14-state chromatin state model to characterize loci-specific histone acetylation at p3000-associated enhancers in early myoblast differentiation, particularly when it is recruited by MyoD 12 . Our data presents a model of histone acetylation increases at distinct genomic loci despite a global decrease in histone acetylation as myoblasts differentiate 12 .…”

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confidence: 99%

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Dissecting myogenin-mediated retinoid X receptor signaling in myogenic differentiation

et al. 2020

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Deciphering the molecular mechanisms underpinning myoblast differentiation is a critical step in developing the best strategy to promote muscle regeneration in patients suffering from muscle-related diseases. We have previously established that a rexinoid x receptor (RXR)-selective agonist, bexarotene, enhances the differentiation and fusion of myoblasts through a direct regulation of MyoD expression, coupled with an augmentation of myogenin protein. Here, we found that RXR signaling associates with the distribution of myogenin at poised enhancers and a distinct E-box motif. We also found an association of myogenin with rexinoid-responsive gene expression and identified an epigenetic signature related to histone acetyltransferase p300. Moreover, RXR signaling augments residue-specific histone acetylation at enhancers co-occupied by p300 and myogenin. Thus, genomic distribution of transcriptional regulators is an important designate for identifying novel targets as well as developing therapeutics that modulate epigenetic landscape in a selective manner to promote muscle regeneration.

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Section: Discussionmentioning

confidence: 79%

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confidence: 99%

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confidence: 99%

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Dissecting myogenin-mediated retinoid X receptor signaling in myogenic differentiation

et al. 2020

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“…Based on genes down‐regulated in PCKO mice, the activity of two central transcription factors in muscle, MEF2A and MYOD, was predicted to be reduced. Both p300 and CBP have previously been described in in vitro studies to interact with and coactivate MYOD and the MEF2 family member MEF2C . Thus, we speculate that the broad down‐regulation of muscle gene programs in PCKO mice could stem from the role of p300 and CBP in coactivating these, and other, myogenic transcription factors.…”

Section: Discussionmentioning

confidence: 72%

p300 and cAMP response element‐binding protein‐binding protein in skeletal muscle homeostasis, contractile function, and survival

Svensson

LaBarge

Sathe

et al. 2020

J cachexia sarcopenia muscle

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Background Reversible ε-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function are unknown. In this study, we investigated the role of the related acetyltransferases p300 and cAMP response element-binding protein-binding protein (CBP) in skeletal muscle transcriptional homeostasis and physiology in adult mice. Methods Mice with skeletal muscle-specific and inducible knockout of p300 and CBP (PCKO) were generated by crossing mice with a tamoxifen-inducible Cre recombinase expressed under the human α-skeletal actin promoter with mice having LoxP sites flanking exon 9 of the Ep300 and Crebbp genes. Knockout of PCKO was induced at 13-15 weeks of age via oral gavage of tamoxifen for 5 days to both PCKO and littermate control [wildtype (WT)] mice. Body composition, food intake, and muscle function were assessed on day 0 (D0) through 5 (D5). Microarray and tandem mass tag mass spectrometry analyses were performed to assess global RNA and protein levels in skeletal muscle of PCKO and WT mice.Results At D5 after initiating tamoxifen treatment, there was a reduction in body weight (À15%), food intake (À78%), stride length (À46%), and grip strength (À45%) in PCKO compared with WT mice. Additionally, ex vivo contractile function [tetanic tension (kPa)] was severely impaired in PCKO vs. WT mice at D3 (~70-80% lower) and D5 (~80-95% lower) and resulted in lethality within 1 week-a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The impaired muscle function in PCKO mice was paralleled by substantial transcriptional alterations (3310 genes; false discovery rate < 0.1), especially in gene networks central to muscle contraction and structural integrity. This transcriptional uncoupling was accompanied by changes in protein expression patterns indicative of impaired muscle function, albeit to a smaller magnitude (446 proteins; fold-change > 1.25; false discovery rate < 0.1). Conclusions These data reveal that p300 and CBP are required for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle and, ultimately, organism survival. By extension, modulating p300/CBP function may hold promise for the treatment of disorders characterized by impaired contractile function in humans.

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“…Conversely untreated and treated OA myoblasts did not display positivity in the nucleus. The increase of histone H4 acetylation in myoblast and satellite cells has been pointed out as an indicator of differentiation and genes transcription, especially of MyoD related genes [32]. Therefore, in cultured myoblats from OP and OA patients we evaluated the effect of CLU conditioning on a myoblast terminal differentiation marker, MYOG.…”

Section: Resultsmentioning

confidence: 99%

Clusterin silencing restores myoblasts viability and down modulates the inflammatory process in osteoporotic disease

et al. 2019

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Background Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Clusterin (CLU) is a glycoprotein involved in inflammation, proliferation, cell death, neoplastic disease, Alzheimer disease and aging. The present study focuses on the expression and the role of CLU in influencing the decrease of muscle mass and fiber senescence in OP-OA condition. Methods Vastus lateralis muscle biopsies were collected from 20 women with OP undergoing surgery for fragility hip fracture and 20 women undergoing arthroplasty for hip osteoarthritis. Results We found an overexpression of CLU in degenerated fibers in OP closely correlated with interleukin 6 (IL6) and histone H4 acetylation level. Conversely, in OA muscle tissues we observed a weak expression of CLU but no nuclear histone H4 acetylation. Ex vivo studies on isolated human myoblasts confirmed CLU overexpression in OP as compared to OA (p < 0.001). CLU treatment of isolated OP and OA myoblasts showed: modulation of proliferation, morphological changes, increase of histone H4 acetylation and induction of myogenin (MYOG) activation in OP myoblast only. In OP condition, functional knockdown of CLU by siRNA restores proliferative myoblasts capability and tissue damage repair, carried out by an evident upregulation of Transglutaminase 2 (TGM2). We also observed downmodulation of CX3CR1 expression with consequent impairing of the inflammatory infiltrate recruitment. Conclusions Results obtained suggest a potential role of CLU in OP by influencing myoblasts terminal differentiation, epigenetic regulation of muscle cell differentiation and senescence. Moreover, CLU silencing points out its role in the modulation of tissue damage repair and inflammation, proposing it as a new diagnostic marker for muscle degeneration and a potential target for specific therapeutic intervention in OP related sarcopenia.

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Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

Cited by 16 publications

References 63 publications

Dissecting myogenin-mediated retinoid X receptor signaling in myogenic differentiation

Dissecting myogenin-mediated retinoid X receptor signaling in myogenic differentiation

p300 and cAMP response element‐binding protein‐binding protein in skeletal muscle homeostasis, contractile function, and survival

Clusterin silencing restores myoblasts viability and down modulates the inflammatory process in osteoporotic disease

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