HMGB2 regulates satellite-cell-mediated skeletal muscle regeneration through IGF2BP2

ABSTRACT Although the mechanism underlying modulation of transcription factors in myogenesis has been well elucidated, the function of the transcription cofactors involved in this process remains poorly understood. Here, we identified HMGB2 as an essential nuclear transcriptional co-regulator in myogenesis. HMGB2 was highly expressed in undifferentiated myoblasts and regenerating muscle. Knockdown of HMGB2 inhibited myoblast proliferation and stimulated its differentiation. HMGB2 depletion downregulated Myf5 and cyclin A2 at the protein but not mRNA level. In contrast, overexpression of HMGB2 promoted Myf5 and cyclin A2 protein upregulation. Furthermore, we found that the RNA-binding protein IGF2BP2 is a downstream target of HMGB2, as previously shown for HMGA2. IGF2BP2 binds to mRNAs of Myf5 or cyclin A2, resulting in translation enhancement or mRNA stabilization, respectively. Notably, overexpression of IGF2BP2 could partially rescue protein levels of Myf5 and cyclin A2, in response to HMGB2 decrease. Moreover, depletion of HMGB2 in vivo severely attenuated muscle repair; this was due to a decrease in satellite cells. Taken together, these results highlight the previously undiscovered and crucial role of the HMGB2–IGF2BP2 axis in myogenesis and muscle regeneration. Summary: HMGB2 promotes myoblast proliferation and muscle regeneration through IGF2BP2, which regulates the protein production of cyclin A2 and Myf5.

[1]  M. Rudnicki,et al.  Wnt signaling in myogenesis. , 2012, Trends in cell biology.

[2]  N. Katsanis,et al.  Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry , 2011, Nature Cell Biology.

[3]  K. Marchal,et al.  Differential regulation of the insulin‐like growth factor II mRNA‐binding protein genes by architectural transcription factor HMGA2 , 2004, FEBS letters.

[4]  E. Hay.  Skeletal-muscle regeneration. , 1971 .

[5]  R. Bryson-Richardson,et al.  The genetics of vertebrate myogenesis , 2008, Nature Reviews Genetics.

[6]  M. Bianchi,et al.  HMGB proteins and gene expression. , 2003, Current opinion in genetics & development.

[7]  A. Corbett,et al.  RNA-binding proteins and gene regulation in myogenesis. , 2011, Trends in pharmacological sciences.

[8]  M. Rudnicki,et al.  The emerging biology of satellite cells and their therapeutic potential. , 2008, Trends in molecular medicine.

[9]  Seth M. Kelly,et al.  Messenger RNA Export from the Nucleus: A Series of Molecular Wardrobe Changes , 2009, Traffic.

[10]  T. Hudson,et al.  Analysis of early C2C12 myogenesis identifies stably and differentially expressed transcriptional regulators whose knock-down inhibits myoblast differentiation. , 2012, Physiological genomics.

[11]  Michiteru Yoshida,et al.  HMGB proteins and transcriptional regulation. , 2010, Biochimica et biophysica acta.

[12]  B. Maček,et al.  Ubiquitin‐dependent regulation of MEKK2/3‐MEK5‐ERK5 signaling module by XIAP and cIAP1 , 2014, The EMBO journal.

[13]  J. Tidball,et al.  Regulatory interactions between muscle and the immune system during muscle regeneration. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[14]  A. Behrens,et al.  c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex , 2011, Nature.

[15]  Jong-Sun Kang,et al.  Muscle stem cells in developmental and regenerative myogenesis , 2010, Current opinion in clinical nutrition and metabolic care.

[16]  E. Rajpert-De Meyts,et al.  Nuclear transit of human zipcode-binding protein IMP1. , 2003, The Biochemical journal.

[17]  F. Hu,et al.  Comparative study on the stem cell phenotypes of C6 cells under different culture conditions. , 2011, Chinese medical journal.

[18]  J. Avruch,et al.  mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. , 2011, Genes & development.

[19]  I. Clay,et al.  A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation. , 2015, Developmental cell.

[20]  M. Bustin,et al.  HMG chromosomal proteins in development and disease. , 2007, Trends in cell biology.

[21]  Jennifer A. Lawson,et al.  Satellite cells , connective tissue fibroblasts and their interactions are crucial for muscle regeneration , 2022 .

[22]  K. Patel,et al.  Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration , 2008, Journal of Cell Science.

[23]  S. Paturi,et al.  Acetaminophen improves protein translational signaling in aged skeletal muscle. , 2010, Rejuvenation research.

[24]  L. Chodosh,et al.  Inducible and coupled expression of the polyomavirus middle T antigen and Cre recombinase in transgenic mice: an in vivo model for synthetic viability in mammary tumour progression , 2014, Breast Cancer Research.

[25]  C. Caron,et al.  HMGB4, a Novel Member of the HMGB Family, Is Preferentially Expressed in the Mouse Testis and Localizes to the Basal Pole of Elongating Spermatids1 , 2009, Biology of reproduction.

[26]  K. Hochedlinger,et al.  Efficient Generation of iPS Cells from Skeletal Muscle Stem Cells , 2011, PloS one.

[27]  P. Rigby,et al.  Gene regulatory networks and transcriptional mechanisms that control myogenesis. , 2014, Developmental cell.

[28]  Micah J. McCauley,et al.  Dual binding modes for an HMG domain from human HMGB2 on DNA. , 2005, Biophysical journal.

[29]  M. Bianchi,et al.  HMG proteins: dynamic players in gene regulation and differentiation. , 2005, Current opinion in genetics & development.

[30]  M. Rudnicki,et al.  Cellular and molecular regulation of muscle regeneration. , 2004, Physiological reviews.

[31]  F. Nielsen,et al.  Cytoplasmic trafficking of IGF-II mRNA-binding protein by conserved KH domains. , 2002, Journal of cell science.

[32]  Y. Kawakami,et al.  Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway , 2009, Proceedings of the National Academy of Sciences.

[33]  Yunyu Zhang,et al.  An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis. , 2012, Developmental cell.

[34]  F. Bost,et al.  A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells , 2005, Oncogene.

[35]  T. Hawke,et al.  Skeletal muscle regeneration is delayed by reduction in Xin expression: consequence of impaired satellite cell activation? , 2012, American journal of physiology. Cell physiology.

[36]  V. Maréchal,et al.  High-mobility group protein HMGB2 regulates human erythroid differentiation through trans-activation of GFI1B transcription. , 2010, Blood.

[37]  Y. Kawakami,et al.  Expression Patterns and Function of Chromatin Protein HMGB2 during Mesenchymal Stem Cell Differentiation* , 2011, The Journal of Biological Chemistry.

[38]  B. Bonavida,et al.  Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide. , 2015, Nitric oxide : biology and chemistry.

[39]  Jordan M. Komisarow,et al.  RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts , 2006, Nature Protocols.

[40]  H. Schöler,et al.  Reduced fertility and spermatogenesis defects in mice lacking chromosomal protein Hmgb2. , 2001, Development.

[41]  M. Rudnicki,et al.  Oct4 Interaction with Hmgb2 Regulates Akt Signaling and Pluripotency , 2013, Stem cells.

[42]  J. Wilusz,et al.  Consequences of mRNA Wardrobe Malfunctions , 2010, Cell.

[43]  W. Kistler,et al.  Levels of chromosomal protein high mobility group 2 parallel the proliferative activity of testis, skeletal muscle, and other organs. , 1979, The Journal of biological chemistry.

[44]  T. Taniguchi,et al.  High-mobility group box family of proteins: ligand and sensor for innate immunity. , 2012, Trends in immunology.

[45]  R. Sciot,et al.  HMGA2 Regulates Transcription of the Imp2 Gene via an Intronic Regulatory Element in Cooperation with Nuclear Factor-κB , 2007, Molecular Cancer Research.

[46]  Gi Fay Mok,et al.  Many routes to the same destination: lessons from skeletal muscle development. , 2011, Reproduction.

[47]  Michael Bustin,et al.  Regulation of DNA-Dependent Activities by the Functional Motifs of the High-Mobility-Group Chromosomal Proteins , 1999, Molecular and Cellular Biology.

[48]  I. Seiliez,et al.  Leucine limitation regulates myf5 and myoD expression and inhibits myoblast differentiation. , 2012, Experimental cell research.

[49]  Andrew S. Dixon,et al.  Disruption of Bcr-Abl Coiled Coil Oligomerization by Design* , 2011, The Journal of Biological Chemistry.

[50]  Anjali A. Sarkar,et al.  Hectd1 regulates intracellular localization and secretion of Hsp90 to control cellular behavior of the cranial mesenchyme , 2012, The Journal of cell biology.