Modeling the regulatory network of histone acetylation in Saccharomyces cerevisiae.
Acetylation of histones plays an important role in regulating transcription. Histone acetylation is mediated partly by the recruitment of specific histone acetyltransferases (HATs) and deacetylases (HDACs) to genomic loci by transcription factors, resulting in modulation of gene expression. Although several specific interactions between transcription factors and HATs and HDACs have been elaborated in Saccharomyces cerevisiae, the full regulatory network remains uncharacterized. We have utilized a linear regression of optimized sigmoidal functions to correlate transcription factor binding patterns to the acetylation profiles of 11 lysines in the four core histones measured at all S. cerevisiae promoters. The resulting associations are combined with large-scale protein-protein interaction data sets to generate a comprehensive model that relates recruitment of specific HDACs and HATs to transcription factors and their target genes and the resulting effects on individual lysines. This model provides a broad and detailed view of the regulatory network, describing which transcription factors are most significant in regulating acetylation of specific lysines at defined promoters. We validate the model, both computationally and experimentally, to demonstrate that it yields accurate predictions of these regulatory mechanisms.
Pham
Hung
H
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Ferrari
Roberto
R
Cokus
Shawn J
SJ
Kurdistani
Siavash K
SK
Pellegrini
Matteo
M
D000107:Acetylation; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D005800:Genes, Fungal; D051548:Histone Acetyltransferases / Q000378:metabolism; D042421:Histone Code; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D008239:Lysine