Dynamic enhancers control skeletal muscle identity and reprogramming

Ramachandran, Krithika; Senagolage, Madhavi D.; Sommars, Meredith A; Futtner, Christopher R.; Omura, Yasuhiro; Allred, Amanda L.; Barish, Grant D.

doi:10.1371/journal.pbio.3000467

Cited by 41 publications

(55 citation statements)

References 94 publications

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“…The genome-wide chromatin landscape of adult muscles had not been evaluated previously at the myofiber level, due to the lack of adapted experimental protocols (Ramachandran et al, 2019). We show here that snATAC-seq is a powerful tool to overcome this limitation and that it allows to detect all the cell populations identified by snRNA-seq in adult skeletal muscles, including myofibers.…”

Section: Discussionmentioning

confidence: 89%

“…Recent studies profiled the genome-wide chromatin accessibility of adult skeletal muscles (Ramachandran et al, 2019). However, this global approach did not discriminate the chromatin status of each cell population present in skeletal muscles.…”

Section: Snatac-seq Reveals Heterogenous Transcriptional Programs In mentioning

confidence: 99%

“…This suggests that the expression of Myh1 and Myh2 in the soleus is less under the control of innervation than the expression of Myh4 in fast muscles. Knowing that in adult myofibers the homeoprotein SIX1 controls the expression of many fast/glycolytic muscle genes among which fMyh genes (Sakakibara et al, 2014;Sakakibara et al, 2016) and that SIX binding motifs accessibility are enriched in Myh4 myonuclei ( (Ramachandran et al, 2019), Figure 3C), we looked at the nuclear accumulation of this protein in fast myonuclei along EDL myofibers.…”

Section: Innervation Controls Myonuclei Coordination Along the Myofibermentioning

confidence: 99%

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Single-nucleus RNA-seq and FISH reveal coordinated transcriptional activity in mammalian myofibers

Santos

Backer

Saintpierre

et al. 2020

Preprint

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Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. By snRNA-seq and snATAC-seq, we showed that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we showed that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a unique mechanism of coordination of gene expression in a syncytium. Introduction:

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Section: Discussionmentioning

confidence: 89%

Section: Snatac-seq Reveals Heterogenous Transcriptional Programs In mentioning

confidence: 99%

Section: Innervation Controls Myonuclei Coordination Along the Myofibermentioning

confidence: 99%

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Single-nucleus RNA-seq and FISH reveal coordinated transcriptional activity in mammalian myofibers

Santos

Backer

Saintpierre

et al. 2020

Preprint

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“…SnATAC-seq identifies heterogenous transcriptional programs in myonuclei. Recent studies profiled the genome-wide chromatin accessibility of adult skeletal muscles 26 . However, this global approach did not discriminate the chromatin status of each cell population present in skeletal muscles.…”

Section: Resultsmentioning

confidence: 99%

Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers

Santos¹,

Backer²,

Saintpierre³

et al. 2020

Nat Commun

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212

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Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.

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“…Although skeletal muscle respiratory capacity and mass appear to be preserved during the seasonal molt, gene ontology suggests a downregulation of genes associated with mechanotransduction of force in skeletal muscle including focal adhesion, and ECM components. Increased mechanical loading in skeletal muscle typically results in an upregulation of collagen as well as proteoglycans and other components of the ECM ( Kjaer, 2004 ; Ramachandran et al, 2019 ). Conversely, skeletal muscle unloading results in decreased transcriptional expression of ECM components including collagen genes ( Savolainen et al, 1987 ; Seene et al, 2012 ), with as little as 48 h of unloading required for decreased gene expression ( Urso et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Changes in Northern Elephant Seal Skeletal Muscle Following Thirty Days of Fasting and Reduced Activity

et al. 2020

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Northern elephant seals (NES, Mirounga angustirostris ) undergo an annual molt during which they spend ∼40 days fasting on land with reduced activity and lose approximately one-quarter of their body mass. Reduced activity and muscle load in stereotypic terrestrial mammalian models results in decreased muscle mass and capacity for force production and aerobic metabolism. However, the majority of lost mass in fasting female NES is from fat while muscle mass is largely preserved. Although muscle mass is preserved, potential changes to the metabolic and contractile capacity are unknown. To assess potential changes in NES skeletal muscle during molt, we collected muscle biopsies from 6 adult female NES before the molt and after ∼30 days at the end of the molt. Skeletal muscle was assessed for respiratory capacity using high resolution respirometry, and RNA was extracted to assess changes in gene expression. Despite a month of reduced activity, fasting, and weight loss, skeletal muscle respiratory capacity was preserved with no change in OXPHOS respiratory capacity. Molt was associated with 162 upregulated genes including those favoring lipid metabolism. We identified 172 downregulated genes including those coding for ribosomal proteins and genes associated with skeletal muscle force transduction and glucose metabolism. Following ∼30 days of molt, NES skeletal muscle metabolic capacity is preserved although mechanotransduction may be compromised. In the absence of exercise stimulus, fasting-induced shifts in muscle metabolism may stimulate pathways associated with preserving the mass and metabolic capacity of slow oxidative muscle.

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Dynamic enhancers control skeletal muscle identity and reprogramming

Cited by 41 publications

References 94 publications

Single-nucleus RNA-seq and FISH reveal coordinated transcriptional activity in mammalian myofibers

Single-nucleus RNA-seq and FISH reveal coordinated transcriptional activity in mammalian myofibers

Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers

Changes in Northern Elephant Seal Skeletal Muscle Following Thirty Days of Fasting and Reduced Activity

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