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Eutherian BetaM, a Muscle‐Specific Integral Protein of Inner Nuclear Membrane, is Implicated in Regulation of MyoD Expression
Author(s) -
Modyanov Nikolai,
Pestov Nikolay,
Ahmad Nisar
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1245.18
Subject(s) - myod , myogenesis , biology , transcriptional regulation , myod protein , myocyte , microbiology and biotechnology , regulator , skeletal muscle , regulation of gene expression , pitx2 , gene expression , nuclear protein , gene , transcription factor , genetics , homeobox , endocrinology
Vertebrate X‐chromosome ATP1B4 genes represent a rare instance of the orthologous gene co‐option that radically changed functions of encoded BetaM proteins during evolution. In lower vertebrates, BetaM is a subunit of Na,K‐ATPase located in the cell membrane. In placental mammals, BetaM completely lost its ancestral role and through radical changes in the structure of its N‐terminal domain gained entirely new properties as a skeletal and atrial cardiac muscle‐specific protein of the inner nuclear membrane possessing the ability to regulate gene expression. BetaM expression is strictly temporally regulated being the highest in late fetal and early postnatal myocytes. Here we show that expression of exogenous BetaM in cultured muscle cells up‐regulates expression of endogenous MyoD, a master regulator of myogenesis, both at transcriptional and translational levels. We determined that eutherian BetaM associates with nuclear transcriptional co‐regulator Ski‐interacting protein (SKIP) and both are identified by ChIP assays as components of MyoD transcriptional complex in vivo in rat neonatal skeletal muscle. Presence of BetaM was detected in the DRR but not in PRR and CE regions of the MyoD promoter. According to the results of Electrophoretic Mobility Shift Assays (EMSA) BetaM‐containing transcriptional complexes are bound to specific E‐box4 and CArG elements of the DRR region. Deletion of either E‐box4 or CArG or both in DRR luciferase reporter abolished its activation by BetaM, These findings demonstrate that BetaM is a novel eutherian‐specific transcriptional regulator which is involved in the regulation of MyoD expression during muscle development. Moreover, structural and functional alterations acquired through ATP1B4 gene co‐option and a unique pattern of expression argue that eutherian‐specific BetaM functions are essential, even might be necessary for survival of placental mammals in natural conditions, and that they provide evolutionary advantage. Support or Funding Information Supported by Department of Physiology & Pharmacology, University of Toledo College of Medicine.