Myc influences global chromatin structure.
The family of myc proto-oncogenes encodes transcription factors (c-, N-, and L-Myc) that regulate cell growth and proliferation and are involved in the etiology of diverse cancers. Myc proteins are thought to function by binding and regulating specific target genes. Here we report that Myc proteins are required for the widespread maintenance of active chromatin. Disruption of N-myc in neuronal progenitors and other cell types leads to nuclear condensation accompanied by large-scale changes in histone modifications associated with chromatin inactivation, including hypoacetylation and altered methylation. These effects are largely reversed by exogenous Myc as well as by differentiation and are mimicked by the Myc antagonist Mad1. The first chromatin changes are evident within 6 h of Myc loss and lead to changes in chromatin structure. Myc widely influences chromatin in part through upregulation of the histone acetyltransferase GCN5. This study provides the first evidence for regulation of global chromatin structure by an oncoprotein and may explain the broad effects of Myc on cell behavior and tumorigenesis.
Knoepfler
Paul S
PS
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-4417, USA.
Zhang
Xiao-yong
XY
Cheng
Pei Feng
PF
Gafken
Philip R
PR
McMahon
Steven B
SB
Eisenman
Robert N
RN
D000107:Acetylation; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D006570:Heterochromatin / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000378:metabolism*; D051381:Rats; D013234:Stem Cells / Q000648:ultrastructure; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D002843:Chromatin; D004247:DNA; D006570:Heterochromatin; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D006657:Histones; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C501385:Mad1l1 protein, mouse