METTL3 regulates skeletal muscle specific miRNAs at both transcriptional and post-transcriptional levels

Diao, Li-Ting; Xie, Shu‐Juan; Lei, Hang; Qiu, Xiusheng; Huang, Meng-Chun; Tao, Shuangping; Hou, Yunfei; Hu, Yanxia; Sun, Yujia; Zhang, Qi; Xiao, Zhilong

doi:10.1016/j.bbrc.2021.03.035

Cited by 27 publications

(33 citation statements)

References 31 publications

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“…This effect was reversed by overexpression of METTL3. These findings were in agreement with our recent report showing that METTL3 influenced muscle-specific miRNAs at both the transcriptional and posttranscriptional levels to block the myogenesis process (Diao et al, 2021a). In addition, we showed that YTHDF1mediated translation was likely critical for m 6 A-modified MNK2 in muscle cells.…”

Section: Discussionsupporting

confidence: 93%

“…Our most recent study confirmed that the m 6 A key methyltransferase METTL3 is involved in the biogenesis of muscle-specific miRNAs (Diao et al, 2021a). This finding is consistent with a previous report indicating that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type specific manner (Alarcón et al, 2015).…”

Section: Introductionsupporting

confidence: 92%

“…m 6 A-RIP qPCR m 6 A methylated RNA immunoprecipitation was performed as we previously described (Diao et al, 2021a). Briefly, 200 µg total RNA were incubated with 8 µg m 6 A antibody (#202003, Synaptic Systems, Germany) for 2 h on a rotating wheel at 4 • C. Then, 50 µL protein A/G magnetic beads were added to reaction mixtures for 2 h on a rotating wheel at 4 • C. After washed three times, beads were incubated with DNase I at 37 • C for 30 min and were then digested by Proteinase K for about 2 h at 37 • C with rotation.…”

Section: Rna Extraction and Quantitative Rt-pcr Analysismentioning

confidence: 99%

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Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration

Xie

Lei

Yang

et al. 2021

Front. Cell Dev. Biol.

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N6-methyladenosine (m6A) RNA methylation has emerged as an important factor in various biological processes by regulating gene expression. However, the dynamic profile, function and underlying molecular mechanism of m6A modification during skeletal myogenesis remain elusive. Here, we report that members of the m6A core methyltransferase complex, METTL3 and METTL14, are downregulated during skeletal muscle development. Overexpression of either METTL3 or METTL14 dramatically blocks myotubes formation. Correspondingly, knockdown of METTL3 or METTL14 accelerates the differentiation of skeletal muscle cells. Genome-wide transcriptome analysis suggests ERK/MAPK is the downstream signaling pathway that is regulated to the greatest extent by METTL3/METTL14. Indeed, METTL3/METTL14 expression facilitates ERK/MAPK signaling. Via MeRIP-seq, we found that MNK2, a critical regulator of ERK/MAPK signaling, is m6A modified and is a direct target of METTL3/METTL14. We further revealed that YTHDF1 is a potential reader of m6A on MNK2, regulating MNK2 protein levels without affecting mRNA levels. Furthermore, we discovered that METTL3/14-MNK2 axis was up-regulated notably after acute skeletal muscle injury. Collectively, our studies revealed that the m6A writers METTL3/METTL14 and the m6A reader YTHDF1 orchestrate MNK2 expression posttranscriptionally and thus control ERK signaling, which is required for the maintenance of muscle myogenesis and may contribute to regeneration.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionsupporting

confidence: 92%

Section: Rna Extraction and Quantitative Rt-pcr Analysismentioning

confidence: 99%

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Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration

Xie

Lei

Yang

et al. 2021

Front. Cell Dev. Biol.

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“…Our recent study elaborated the dynamic m 6 A methylation of mRNA during skeletal muscle differentiation and revealed the role of METTL3/14-m 6 A-MNK2-ERK signaling axis in skeletal muscle differentiation and regeneration ( Xie et al, 2021b ). Besides, another work of us confirmed that the m 6 A key methyltransferase METTL3 is involved in the biogenesis of muscle-specific miRNAs ( Diao et al, 2021a ). This finding is consistent with a previous report indicating that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type specific manner ( Alarcón et al, 2015 ).…”

Section: Introductionmentioning

confidence: 83%

“…m 6 A-IP-qPCR m 6 A methylated RNA immunoprecipitation was performed as previously described (Diao et al, 2021a). Briefly, 200 µg of total RNA was incubated with 8 µg of m 6 A-specific antibody (Synaptic Systems, 202003) for 2 h at 4 • C with gentle rotation.…”

Section: Merip Sequencingmentioning

confidence: 99%

Characterization of Long Non-coding RNAs Modified by m6A RNA Methylation in Skeletal Myogenesis

Xie

Tao

Diao

et al. 2021

Front. Cell Dev. Biol.

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Proper development of mammalian skeletal muscle relies on precise gene expression regulation. Our previous studies revealed that muscle development is regulated by both mRNA and long non-coding RNAs (lncRNAs). Accumulating evidence has demonstrated that N6-methyladenosine (m6A) plays important roles in various biological processes, making it essential to profile m6A modification on a transcriptome-wide scale in developing muscle. Patterns of m6A methylation in lncRNAs in developing muscle have not been uncovered. Here, we reveal differentially expressed lncRNAs and report temporal m6A methylation patterns in lncRNAs expressed in mouse myoblasts and myotubes by RNA-seq and methylated RNA immunoprecipitation (MeRIP) sequencing. Many lncRNAs exhibit temporal differential expression, and m6A-lncRNAs harbor the consensus m6A motif “DRACH” along lncRNA transcripts. Interestingly, we found that m6A methylation levels of lncRNAs are positively correlated with the transcript abundance of lncRNAs. Overexpression or knockdown of m6A methyltransferase METTL3 alters the expression levels of these lncRNAs. Furthermore, we highlight that the function of m6A genic lncRNAs might correlate to their nearby mRNAs. Our work reveals a fundamental expression reference of m6A-mediated epitranscriptomic modifications in lncRNAs that are temporally expressed in developing muscle.

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The importance of RNA modifications: From cells to muscle physiology

2021

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Naturally occurring post-transcriptional chemical modifications serve critical roles in impacting RNA structure and function. More directly, modifications may affect RNA stability, intracellular transport, translational efficiency, and fidelity. The combination of effects caused by modifications are ultimately linked to gene expression regulation at a genome-wide scale. The latter is especially true in systems that undergo rapid metabolic and or translational remodeling in response to external stimuli, such as the presence of stressors, but beyond that, modifications may also affect cell homeostasis. Although examples of the importance of RNA modifications in translation are accumulating rapidly, still what these contribute to the function of complex physiological systems such as muscle is only recently emerging. In the present review, we will introduce key information on various modifications and highlight connections between those and cellular malfunctions. In passing, we will describe well-documented roles for modifications in the nervous system and use this information as a stepping stone to emphasize a glaring paucity of knowledge on the role of RNA modifications in heart and skeletal muscle, with particular emphasis on mitochondrial function in those systems.

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METTL3 regulates skeletal muscle specific miRNAs at both transcriptional and post-transcriptional levels

Cited by 27 publications

References 31 publications

Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration

Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration

Characterization of Long Non-coding RNAs Modified by m6A RNA Methylation in Skeletal Myogenesis

The importance of RNA modifications: From cells to muscle physiology

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