Ruolo del gene PC4 (IFRD1) nel differenziamento muscolare
Author(s)
Conti, Filippo
Date Issued
April 4, 2008
Type
Doctoral Thesis
Abstract
Histone deacetylase 4 (HDAC4) negatively regulates skeletal myogenesis by associating with the myocyte
enhancer factor 2 (MEF2) transcription factors. Our data indicate that the gene PC4 (interferon-related
developmental regulator 1 [IFRD1], Tis7), which we have previously shown to be required for myoblast
differentiation, is both induced by MyoD and potentiates the transcriptional activity of MyoD, thus revealing a positive regulatory loop between these molecules. Enhancement by PC4 of MyoD-dependent activation of muscle gene promoters occurs selectively through MEF2 binding sites. Furthermore, PC4 localizes in the nucleus of differentiating myoblasts, associates with MEF2C, and is able to counteract the HDAC4-mediated inhibition of MEF2C. This latter action can be explained by the observed ability of PC4 to dose dependently displace HDAC4 from MEF2C. Consistently, we have observed that (i) the region of PC4 that binds MEF2C is sufficient to counteract the inhibition by HDAC4; (ii) PC4, although able to bind HDAC4, does not inhibit the enzymatic activity of HDAC4.Together, our findings strongly suggest that PC4 acts as a coactivator of MyoD and MEF2C by removing the inhibitory effect of HDAC4, thus exerting a pivotal function during myogenesis.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
Subjects