Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction

Liu, Lingli; Ding, Chenyun; Fu, Tingting; Feng, Zhenhua; Lee, Jieun; Xiao, Liwei; Xu, Zhihong; Yin, Yujing; Guo, Qiqi; Sun, Zongchao; Sun, Wanping; Mao, Yan; Yang, Likun; Zhou, Zheng; Zhou, Danxia; Xu, Leilei; Zhu, Zezhang; Qiu, Yong; Ge, Kai; Gan, Zhenji

doi:10.1172/jci136155

Cited by 39 publications

(47 citation statements)

References 56 publications

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“…Transcriptomics analyses were performed using RNA-sequencing as described previously [ 48 , 49 ]. Total RNA was isolated from the entire gastrocnemius muscle of 8-week-old male Fnip1 KO , Fnip1 TgKO and WT control mice using RNAiso Plus (Takara Bio).…”

Section: Methodsmentioning

confidence: 99%

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

et al. 2021

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Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.

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Section: Methodsmentioning

confidence: 99%

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

et al. 2021

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“…For the genes coding for contractile and calcium handling proteins, the differences in the epigenome were not only restricted to the promoter regions, but also the inter-and intragenic areas with H3K27ac enrichment, such as the enhancer located inside the MyHC cluster at chromosome 11 between the long non-coding RNA Linc-Myh and Myh2 (MyHC-2A) promoting fast glycolytic phenotype [77], and upstream enhancer regions at the slow isoforms of Myh7 (MyHC-1) and Atp2a2 (SERCA2) genes [78] (Figs 4B and 5). Furthermore, we also identified the recently discovered fast phenotype specific enhancer located in the locus coding for the Pvalb (Parvalbumin) gene [42].…”

Section: Plos Geneticsmentioning

confidence: 99%

“…In the latter case, the transcription factor, together with its coregulator, establishes an open chromatin environment at active enhancers that enforce an oxidative/slow muscle phenotype, e.g. by regulating sarcomeric slow genes such as Myh7 (MyHC-1) and Tnnc1 (Troponin C1) through enhancers located upstream of their respective promoters [78]. MEF2C is also participating in activity-related calcium regulation, both by being activated by upstream regulators, such as MAPK and calmodulin-dependent protein kinases (CaMK) [110][111][112], but also through regulation of the genes participating in the signaling cascades [113][114][115].…”

Section: Plos Geneticsmentioning

confidence: 99%

Comparing the epigenetic landscape in myonuclei purified with a PCM1 antibody from a fast/glycolytic and a slow/oxidative muscle

et al. 2021

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Muscle cells have different phenotypes adapted to different usage, and can be grossly divided into fast/glycolytic and slow/oxidative types. While most muscles contain a mixture of such fiber types, we aimed at providing a genome-wide analysis of the epigenetic landscape by ChIP-Seq in two muscle extremes, the fast/glycolytic extensor digitorum longus (EDL) and slow/oxidative soleus muscles. Muscle is a heterogeneous tissue where up to 60% of the nuclei can be of a different origin. Since cellular homogeneity is critical in epigenome-wide association studies we developed a new method for purifying skeletal muscle nuclei from whole tissue, based on the nuclear envelope protein Pericentriolar material 1 (PCM1) being a specific marker for myonuclei. Using antibody labelling and a magnetic-assisted sorting approach, we were able to sort out myonuclei with 95% purity in muscles from mice, rats and humans. The sorting eliminated influence from the other cell types in the tissue and improved the myo-specific signal. A genome-wide comparison of the epigenetic landscape in EDL and soleus reflected the differences in the functional properties of the two muscles, and revealed distinct regulatory programs involving distal enhancers, including a glycolytic super-enhancer in the EDL. The two muscles were also regulated by different sets of transcription factors; e.g. in soleus, binding sites for MEF2C, NFATC2 and PPARA were enriched, while in EDL MYOD1 and SIX1 binding sites were found to be overrepresented. In addition, more novel transcription factors for muscle regulation such as members of the MAF family, ZFX and ZBTB14 were identified.

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“…Interestingly, MEF2C and its family members are known to interact with co-regulators that are capable in altering the epigenetic environment such as histone acetyl transferase P300 (94,95) and lysine methyltransferase Myeloid/lymphoid or Mixed-Lineage Leukemia 4 (MLL4). In the latter case, the transcription factor together with its co-regulator establish an open chromatin environment at active enhancers that enforces an oxidative/slow muscle phenotype e. g. by regulating sarcomeric slow genes such as Myh7 (MyHC-1) and Tnnc1 (Troponin C1) through enhancers located upstream of their respective promoters (67). MEF2C is also participating in muscle activity-related calcium regulation, both by being activated by downstream signaling pathways such as MAPK and calmodulin-dependent protein kinases (CaMK) (96-98), but also through regulation of the genes participating in the signaling cascades (99)(100)(101).…”

Section: Discussionmentioning

confidence: 99%

The epigenetic landscape in purified myonuclei from fast and slow muscles

Bengtsen

Eftestøl

et al. 2021

Preprint

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Muscle cells have different phenotypes adapted to different usage and can be grossly divided into fast/glycolytic and slow/oxidative types. While most muscles contain a mixture of such fiber types, we aimed at providing a genome-wide analysis of chromatin environment by ChIP-Seq in two muscle extremes, the almost completely fast/glycolytic extensor digitorum longus (EDL) and slow/oxidative soleus muscles. Muscle is a heterogeneous tissue where less than 60% of the nuclei are inside muscle fibers. Since cellular homogeneity is critical in epigenome-wide association studies we devised a new method for purifying skeletal muscle nuclei from whole tissue based on the nuclear envelope protein Pericentriolar material 1 (PCM1) being a specific marker for myonuclei. Using antibody labeling and a magnetic-assisted sorting approach we were able to sort out myonuclei with 95% purity. The sorting eliminated influence from other cell types in the tissue and improved the myo-specific signal. A genome-wide comparison of the epigenetic landscape in EDL and soleus reflected the functional properties of the two muscles each with a distinct regulatory program involving distal enhancers, including a glycolytic super-enhancer in the EDL. The two muscles are also regulated by different sets of transcription factors; e.g. in soleus binding sites for MEF2C, NFATC2 and PPARA were enriched, while in EDL MYOD1 and SOX1 binding sites were found to be overrepresented. In addition, novel factors for muscle regulation such as MAF, ZFX and ZBTB14 were identified.

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Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction

Cited by 39 publications

References 56 publications

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

Comparing the epigenetic landscape in myonuclei purified with a PCM1 antibody from a fast/glycolytic and a slow/oxidative muscle

The epigenetic landscape in purified myonuclei from fast and slow muscles

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