Epigenetic regulation and the variability of gene expression

We characterized the genetic variability of gene expression in terms of trans and cis variability for each yeast transcript. Genes that are highly regulated by nucleosomes showed a high degree of trans variability. From the expression profiles of mutants for various chromatin modifiers, we found that trans-variable genes are distinctly regulated at the chromatin level. The effect of chromatin regulators was highly significant, even when compared with that of transcription factors. The DNA-binding activities of transcription factors had a low influence on trans variability. In the case of the basal transcription factor TBP and TBP-associated factor TAF1, expression variability was coupled with the histone acetyltransferase activities of TAF1 and other factors, rather than with the binding of TBP to DNA. Additionally, we found that the correlation of TATA-box presence and expression variability could be explained in terms of chromatin regulation. The lack of activating histone modifications may subject TATA-containing promoters to chromatin regulation processes. Our results propose that epigenetic regulation has a central role in the variation and evolution of gene expression.

[1]  D. Pe’er,et al.  Identifying regulatory mechanisms using individual variation reveals key role for chromatin modification , 2006, Proceedings of the National Academy of Sciences.

[2]  Matthew W. Hahn,et al.  The evolution of transcriptional regulation in eukaryotes. , 2003, Molecular biology and evolution.

[3]  B. Pugh,et al.  Identification and Distinct Regulation of Yeast TATA Box-Containing Genes , 2004, Cell.

[4]  B. Franklin Pugh,et al.  Genome-Wide Relationships between TAF1 and Histone Acetyltransferases in Saccharomyces cerevisiae , 2006, Molecular and Cellular Biology.

[5]  John J. Wyrick,et al.  Chromosomal landscape of nucleosome-dependent gene expression and silencing in yeast , 1999, Nature.

[6]  Ron Shamir,et al.  A genome-wide analysis in Saccharomyces cerevisiae demonstrates the influence of chromatin modifiers on transcription , 2007, Nature Genetics.

[7]  Andrew J. Link,et al.  Proteomics of the Eukaryotic Transcription Machinery: Identification of Proteins Associated with Components of Yeast TFIID by Multidimensional Mass Spectrometry , 2002, Molecular and Cellular Biology.

[8]  Michael R. Green,et al.  Dissecting the Regulatory Circuitry of a Eukaryotic Genome , 1998, Cell.

[9]  Megan F. Cole,et al.  Genome-wide Map of Nucleosome Acetylation and Methylation in Yeast , 2005, Cell.

[10]  Rachel B. Brem,et al.  Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors , 2003, Nature Genetics.

[11]  C. Semple,et al.  Chromatin structure and evolution in the human genome , 2007, BMC Evolutionary Biology.

[12]  K. Struhl,et al.  Repression by Ume6 Involves Recruitment of a Complex Containing Sin3 Corepressor and Rpd3 Histone Deacetylase to Target Promoters , 1997, Cell.

[13]  L. Guarente,et al.  Diverse and dynamic functions of the Sir silencing complex , 1999, Nature Genetics.

[14]  Leonid Kruglyak,et al.  Local Regulatory Variation in Saccharomyces cerevisiae , 2005, PLoS genetics.

[15]  B. Pugh,et al.  Interplay of TBP inhibitors in global transcriptional control. , 2002, Molecular cell.

[16]  R. Morse,et al.  Global and specific transcriptional repression by the histone H3 amino terminus in yeast , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  L. Kruglyak,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002, Science.

[18]  B. Pugh,et al.  A role for TBP dimerization in preventing unregulated gene expression. , 1999, Molecular cell.

[19]  Rachel B. Brem,et al.  The landscape of genetic complexity across 5,700 gene expression traits in yeast. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Jung Kyoon Choi,et al.  Environmental Effects on Gene Expression Phenotype Have Regional Biases in the Human Genome , 2007, Genetics.

[21]  Y. Zhao,et al.  Central role of Ifh1p–Fhl1p interaction in the synthesis of yeast ribosomal proteins , 2005, The EMBO journal.

[22]  Michael Karin,et al.  Genetic Properties Influencing the Evolvability of Gene Expression , 2007 .

[23]  P. Bork,et al.  Proteome survey reveals modularity of the yeast cell machinery , 2006, Nature.

[24]  Nicola J. Rinaldi,et al.  Transcriptional regulatory code of a eukaryotic genome , 2004, Nature.

[25]  M. Stephens.  Use of the Kolmogorov-Smirnov, Cramer-Von Mises and Related Statistics without Extensive Tables , 1970 .

[26]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  B. Pugh,et al.  A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae. , 2004, Molecular cell.

[28]  C. Kooperberg,et al.  Widespread Collaboration of Isw2 and Sin3-Rpd3 Chromatin Remodeling Complexes in Transcriptional Repression , 2001, Molecular and Cellular Biology.

[29]  Patrick J. Killion,et al.  Genetic reconstruction of a functional transcriptional regulatory network , 2007, Nature Genetics.

[30]  N. Barkai,et al.  A genetic signature of interspecies variations in gene expression , 2006, Nature Genetics.

[31]  Gary D Bader,et al.  Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry , 2002, Nature.