Abstract
Variation in gene expression is an essential material for biological diversity among single cells1,2,3, individuals4,5,6 and populations or species7,8,9. Here we show that expression variability is an intrinsic property that persists at those different levels. Each promoter seems to have a unique capacity to respond to external signals that can be environmental, genetic or even stochastic. Our investigation into nucleosome organization of variably responding promoters revealed a commonly positioned nucleosome at a critical regulatory region where most transcription start sites and TATA elements are located, a deviation from typical nucleosome-free status. The nucleotide sequences in this region of variable promoters showed a high propensity for DNA bending and a periodic distribution of particular dinucleotides, encoding preferences for DNA–nucleosome interaction. Variable expression is likely to occur during removal of this nucleosome for gene activation. This is a unique example of how promoter sequences intrinsically encode regulatory flexibility, which is vital for biological processes such as adaptation, development and evolution.
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References
Elowitz, M.B., Levine, A.J., Siggia, E.D. & Swain, P.S. Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002).
Blake, W.J. Kærn, M., Cantor, C.R. & Collins, J.J. Noise in eukaryotic gene expression. Nature 422, 633–637 (2003).
Newman, J.R. et al. Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846 (2006).
Brem, R.B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002).
Schadt, E.E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003).
Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).
Tirosh, I., Weinberger, A., Carmi, M. & Barkai, N. A genetic signature of interspecies variations in gene expression. Nat. Genet. 38, 830–834 (2006).
Townsend, J.P., Cavalieri, D. & Hartl, D.L. Population genetic variation in genome-wide gene expression. Mol. Biol. Evol. 20, 955–963 (2003).
Spielman, R.S. et al. Common genetic variants account for differences in gene expression among ethnic groups. Nat. Genet. 39, 226–231 (2007).
Landry, C.R., Lemos, B., Rifkin, S.A., Dickinson, W.J. & Hartl, D.L. Genetic properties influencing the evolvability of gene expression. Science 317, 118–121 (2007).
Choi, J.K. & Kim, Y.-J. Epigenetic regulation and the variability of gene expression. Nat. Genet. 40, 141–147 (2008).
Ahmad, K. & Henikoff, S. Epigenetic consequences of nucleosome dynamics. Cell 111, 281–284 (2002).
Pirrotta, V. & Gross, D.S. Epigenetic silencing mechanisms in budding yeast and fruit fly: different paths, same destinations. Mol. Cell 18, 395–398 (2005).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).
Lee, S.-I., Pe'er, D., Dudley, A.M., Church, G.M. & Koller, D. Identifying regulatory mechanisms using individual variation reveals key role for chromatin modification. Proc. Natl. Acad. Sci. USA 103, 14062–14067 (2006).
Tirosh, I. & Barkai, N. Two strategies for gene regulation by promoter nucleosomes. Genome Res. 18, 1084–1091 (2008).
Lee, W. et al. A high-resolution atlas of nucleosome occupancy in yeast. Nat. Genet. 39, 1235–1244 (2007).
Yuan, G.-C. Genome-scale identification of nucleosome positions in S. cerevisiae. Science 309, 626–630 (2005).
Mavrich, T.N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008).
Ozsolak, F., Song, J.S., Liu, X.S. & Fisher, D.E. High-throughput mapping of the chromatin structure of human promoters. Nat. Biotechnol. 25, 244–248 (2007).
Moreira, J.M. & Holmberg, S. Nucleosome structure of the yeast CHA1 promoter: analysis of activation-dependent chromatin remodeling of an RNA-polymerase-II-transcribed gene in TBP and RNA pol II mutants defective in vivo in response to acidic activators. EMBO J. 17, 6028–6038 (1998).
Segal, E. et al. A genomic code for nucleosome positioning. Nature 442, 772–778 (2006).
Ioshikhes, I.P., Albert, I., Zanton, S.J. & Pugh, B.F. Nucleosome positions predicted through comparative genomics. Nat. Genet. 38, 1210–1215 (2006).
Brukner, I., Sanchez, R., Suck, D. & Pongor, S. Sequence-dependent bending propensity of DNA as revealed by DNase I: parameters for trinucleotides. EMBO J. 14, 1812–1818 (1995).
Gasch, A.P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).
Basehoar, A.D., Zanton, S.J. & Pugh, B.F. Identification and distinct regulation of yeast TATA box-containing genes. Cell 116, 699–709 (2004).
Miura, F. et al. A large-scale full-length cDNA analysis to explore the budding yeast transcriptome. Proc. Natl. Acad. Sci. USA 103, 17846–17851 (2006).
MacIsaac, K.D. et al. An improved map of conserved regulatory sites for Saccharomyces cerevisiae. BMC Bioinformatics 7, 113 (2006).
Fraser, H.B., Hirsh, A.E., Giaever, G., Kumm, J. & Eisen, M.B. Noise mininization in eukaryotic gene expression. PLoS Biol. 2, e137 (2004).
Acknowledgements
This work was supported by grants from the Korean Ministry of Science and Technology to Y.-J.K. (Epigenomic Research of Human Disease and Global Research Lab).
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Supplementary Figures 1 and 2 and Supplementary Tables 2–4 (PDF 616 kb)
Supplementary Table 1
Variability measures, cre, and tre for each yeast gene (XLS 1337 kb)
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Choi, J., Kim, YJ. Intrinsic variability of gene expression encoded in nucleosome positioning sequences. Nat Genet 41, 498–503 (2009). https://doi.org/10.1038/ng.319
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DOI: https://doi.org/10.1038/ng.319
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