Visit our Expo - Redox and Inflammation signaling 2012

Session XIII : Cell signaling pathways leading to regulated chromatin modifications
Poster XIII, 10
Signaling pathways converting extra-cellular cues into chromatin modifications at
muscle specific loci during myogenesis
Cristiano Simone1,2 , Sonia V. Forcales3,
Lucia Latella3, Pier Lorenzo Puri3
1 Sbarro Institute for Cancer Research and Molecular Medicine, Department of
Biology, College of Science and Technology Temple University, Philadelphia PA 19122,
USA. 2 Division of Medical Genetics, Department of Biomedicine in Childhood,
University of Bari, Bari 70124, Italy. 3 DTI at Fondazione A. Cisalpino, ICBTE, Rome
00128, Italy; and The Burnham Institute, La Jolla, San Diego, CA 92093, USA
Myogenic differentiation is a stepwise process influenced by external cues, which are
converted by cytoplasmic cascades into specific chromatin modifications, to coordinate the
transcription of muscle specific genes. For instance, two distinct cytoplasmic cascades, the
p38 and IGF1-mediated PI3K/Akt pathways, transmit to the nucleus pro-differentiation cues
to activate the myogenic program.
We have investigated the individual contribution of these pathways in the regulation of the
assembly of the chromatin-modifying enzymes on muscle-specific promoters. Sequential
recruitment of muscle regulating factors (MRFs), histone acetyltransferases (HATs) and
remodeling complexes (SWI/SNFs) on muscle enhancers/promoters was differently affected
by specific inhibition of PI3K (by LY294002) and p38 (by SB203580), resulting in distinct
patterns of chromatin modifications. While pharmacological blockade of PI3K inhibited
HATs recruitment, thereby preventing acetylation of both histones and MyoD and reducing
the levels of chromatin-bound MyoD, SB203580 (SB) selectively affected SWI/SNF
chromatin binding and remodeling. In both cases, transcription of muscle-specific genes was
inhibited.
This evidence establishes a functional interdependence between IGF-1/PI3K/Akt and p38
pathways in coordinating the assembly of the myogenic transcriptosome, and suggests that
hyperacetylation of muscle enhancers/promoters in myoblasts exposed to IGF-1 precedes
chromatin remodeling, which is induced by p38. The dissection of the events leading to
muscle-specific transcription by pharmacological targeting of individual signaling cascades
could reveal the rationale for manipulating skeletal myogenesis in vivo.
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