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Yin Yang 1 is required for PHD finger protein 20-mediated myogenic differentiation in vitro and in vivo

Abstract

The development of skeletal muscle requires progression of a highly ordered cascade of events comprising myogenic lineage commitment, myoblast proliferation, and terminal differentiation. The process of myogenesis is controlled by several myogenic transcription factors that act as terminal effectors of signaling cascades and produce appropriate developmental stage-specific transcripts. PHD finger protein 20 (PHF20) is a multidomain protein and subunit of a lysine acetyltransferase complex that acetylates histone H4 and p53, but its function is unclear. Notably, it has been reported that PHF20 knockout mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Therefore, the putative role of PHF20 in myogenic differentiation was further investigated. In the present study, we found that protein and mRNA expression levels of PHF20 were decreased during myogenic differentiation in C2C12 cells. At the same time, Yin Yang 1 (YY1) was also decreased during myogenic differentiation. PHF20 overexpression increased YY1 expression during myogenic differentiation, together with a delay in MyoD expression. PHF20 expression enhanced the transcriptional activity of YY1 while shRNA-mediated depletion of PHF20 resulted in the reduction of YY1 promoter activity in C2C12 cells. In addition, PHF20 directly bounds to the YY1 promoter in C2C12 cells. In a similar manner, YY1 expression was elevated while myosin heavy chain expression was decreased in PHF20 transgenic (TG) mice. Histological analysis revealed abnormalities in the shape and length of muscles in PHF20-TG mice. Furthermore, PHF20-TG muscles slowly regenerated after cardiotoxin injection, indicating that PHF20 affected muscle differentiation and regeneration after injury in vivo. Taken together, these results suggested that PHF20 plays an important role in myogenic differentiation by regulating YY1.

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Fig. 1: Changes in PHD finger protein 20 (PHF20) and Yin Yang 1 (YY1) expression during myogenic differentiation in C2C12 cells.
Fig. 2: Effect of PHF20 on myogenic differentiation in C2C12 cells.
Fig. 3: PHF20 directly binds to the promoter of YY1.
Fig. 4: PHF20 inhibits myogenic differentiation marker (MyoD) expression via the YY1 promoter.
Fig. 5: Whole calf muscle and skeletal muscle shape and morphology differ between wild-type (WT) and PHF20 transgenic (TG) mice.
Fig. 6: Overexpression of PHF20 delays muscle regeneration after CTX-injury.
Fig. 7: Schematic illustration of the working model for the role of PHF20 during myogenesis.

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Acknowledgements

This work was financially supported by research fund of Chungnam National University (Jongsun Park) and the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (NRF-2014R1A1A3050752, NRF-2015R1A2A2 A01003597). The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/KMV0G8.

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Lee, H., Hong, Y., Kong, G. et al. Yin Yang 1 is required for PHD finger protein 20-mediated myogenic differentiation in vitro and in vivo. Cell Death Differ 27, 3321–3336 (2020). https://doi.org/10.1038/s41418-020-0580-6

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