Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation.
During muscle regeneration, the mechanism integrating environmental cues at the chromatin of muscle progenitors is unknown. We show that inflammation-activated MKK6-p38 and insulin growth factor 1 (IGF1)-induced PI3K/AKT pathways converge on the chromatin of muscle genes to target distinct components of the muscle transcriptosome. p38 alpha/beta kinases recruit the SWI/SNF chromatin-remodeling complex; AKT1 and 2 promote the association of MyoD with p300 and PCAF acetyltransferases, via direct phosphorylation of p300. Pharmacological or genetic interference with either pathway led to partial assembly of discrete chromatin-bound complexes, which reflected two reversible and distinct cellular phenotypes. Remarkably, PI3K/AKT blockade was permissive for chromatin recruitment of MEF2-SWI/SNF complex, whose remodeling activity was compromised in the absence of MyoD and acetyltransferases. The functional interdependence between p38 and IGF1/PI3K/AKT pathways was further established by the evidence that blockade of AKT chromatin targets was sufficient to prevent the activation of the myogenic program triggered by deliberate activation of p38 signaling.
Serra
Carlo
C
The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037-1062, USA.
Palacios
Daniela
D
Mozzetta
Chiara
C
Forcales
Sonia V
SV
Morantte
Ianessa
I
Ripani
Meri
M
Jones
David R
DR
Du
Keyong
K
Jhala
Ulupi S
US
Simone
Cristiano
C
Puri
Pier Lorenzo
PL
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D048430:Cell Shape; D002843:Chromatin / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D002843:Chromatin; D002867:Chromones; D050881:E1A-Associated p300 Protein; D007093:Imidazoles; D007334:Insulin-Like Growth Factor I; D048669:MAP Kinase Kinase 6; D009025:Morpholines; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D034741:RNA, Small Interfering; D050880:p300-CBP Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099224:p300-CBP-Associated Factor; C057363:MyoD1 myogenic differentiation protein; C519530:insulin-like growth factor-1, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494361:Ep300 protein, mouse; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C482567:Map2k6 protein, mouse; C093642:SB 203580