Gene Expression Profiling of Muscle Stem Cells Identifies Novel Regulators of Postnatal Myogenesis

Abstract

Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties. We have identified multiple genes and pathways associated with satellite cell formation, including set of genes specifically induced (EphA1, EphA2, EfnA1, EphB1, Zbtb4, Zbtb20) or inhibited (EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnBs, Zfp354c, Zcchc5, Hmga2) in adult stem cells. Ephrin receptors and ephrins ligands have been implicated in cell migration and guidance in many tissues including skeletal muscle. Here we show that Ephrin receptors and ephrins ligands are also involved in regulating the adult myogenic program. Strikingly, impairment of EPHB1 function in satellite cells leads to increased differentiation at the expense of self-renewal in isolated myofiber cultures. In addition, we identified new transcription factors, including several zinc finger proteins. ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed, whereas ZBTB4 increased it, and ZBTB20 induced myogenic progression. The architectural and transcriptional regulator HMGA2 was involved in satellite cell activation. Together, our study shows that transcriptome profiling coupled with myofiber culture analysis, provides an efficient system to identify and validate candidate genes implicated in establishment/maintenance of muscle stem cells. Furthermore, tour de force transcriptomic profiling provides a wealth of data to inform for future stem cell-based muscle therapies.

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

“…In line with this observation, GLPG1790 induced a significant up-regulation of MYOD1 and myogenin, followed by increased levels of MyHC protein, a marker of terminal myogenic differentiation, in both ERMS cell lines. The evidence that impairment of EPH-A2 is linked to myogenesis is in accordance with a report describing the role of EPH/Ephrin interactions in regulating the myogenic program at the expense of selfrenewal [36,37]. Contrarily to what expected, Cyclin D1 levels were rapidly and persistently increased by GLPG1790 treatment in comparison to mocked control cells.…”

Three‐dimensional spherical gelatin bubble‐based scaffold improves the myotube formation of H9c2 myoblasts

“…To verify the differentiation processes, the messenger RNA (mRNA) expressions of H9c2 cells cultured on different dimensions with GM or DM were analyzed. MyoG , corresponds to skeletal muscle development, is required during the myogenic fusion of myoblasts (Alonso‐Martin et al, ). ACTA1 is the gene encoding α‐actin, an essential component of sarcomeres which involved in muscle contraction.…”

A co-expression network in hexaploid wheat reveals mostly balanced expression and lack of significant gene loss of homeologous meiotic genes upon polyploidization

“…This gene has been previously reported to have a key role in homologous chromosome pairing, synapsis, DNA recombination and accurate chromosome segregation during meiosis in maize [ 84 ], Arabidopsis [ 85 ] and wheat [ 59 ]. Other hub genes identified in modules 28 and 41 encoded for the high mobility group proteins [ 86-90 ], histone deacetylase [ 91-94 ], and F-box proteins [ 95 ].…”