Mechanistic stochastic model of histone modification pattern formation

Epigenetics & Chromatin

Frank J Bruggeman²  Pernette J Verschure³  Timo R Maarleveld¹  Lisette C M Anink-Groenen³ 

[1] BioSolar Cells, Wageningen, The Netherlands;Systems Bioinformatics, Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands;Swammerdam Institute for Life Science (SILS), University of Amsterdam, Science Park 904, P.O. Box 94215, 1098 GE, Amsterdam, The Netherlands

关键词: Cooperative interactions;    Boundary formation;    Bistable dynamics;    Stochastic mathematical model;    Epigenetics;    Histone modification patterns;    Chromatin structure;   

Others  :  1120485
DOI  :  10.1186/1756-8935-7-30

 received in 2014-07-10, accepted in 2014-10-02,  发布年份 2014

【 摘 要 】

Background

The activity of a single gene is influenced by the composition of the chromatin in which it is embedded. Nucleosome turnover, conformational dynamics, and covalent histone modifications each induce changes in the structure of chromatin and its affinity for regulatory proteins. The dynamics of histone modifications and the persistence of modification patterns for long periods are still largely unknown.

Results

In this study, we present a stochastic mathematical model that describes the molecular mechanisms of histone modification pattern formation along a single gene, with non-phenomenological, physical parameters. We find that diffusion and recruitment properties of histone modifying enzymes together with chromatin connectivity allow for a rich repertoire of stochastic histone modification dynamics and pattern formation. We demonstrate that histone modification patterns at a single gene can be established or removed within a few minutes through diffusion and weak recruitment mechanisms of histone modification spreading. Moreover, we show that strong synergism between diffusion and weak recruitment mechanisms leads to nearly irreversible transitions in histone modification patterns providing stable patterns. In the absence of chromatin connectivity spontaneous and dynamic histone modification boundaries can be formed that are highly unstable, and spontaneous fluctuations cause them to diffuse randomly. Chromatin connectivity destabilizes this synergistic system and introduces bistability, illustrating state switching between opposing modification states of the model gene. The observed bistable long-range and localized pattern formation are critical effectors of gene expression regulation.

Conclusion

This study illustrates how the cooperative interactions between regulatory proteins and the chromatin state generate complex stochastic dynamics of gene expression regulation.

【 授权许可】

   
2014 Anink-Groenen et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Kouzarides T: Chromatin modifications and their function. Cell 2007, 128:693-705.
• [2]Barski A, Cuddapah S, Cui K, Roh T-Y, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K: High-resolution profiling of histone methylations in the human genome. Cell 2007, 129:823-837.
• [3]Turner BM: The adjustable nucleosome: an epigenetic signaling module. Trends Genet 2012, 28:436-444.
• [4]Karlić R, Chung H-R, Lasserre J, Vlahovicek K, Vingron M: Histone modification levels are predictive for gene expression. Proc Natl Acad Sci U S A 2010, 107:2926-2931.
• [5]Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE: Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 2011, 473:43-49.
• [6]Cosgrove MS, Wolberger C: How does the histone code work? Biochem Cell Biol 2005, 83:468-476.
• [7]Barth TK, Imhof A: Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem Sci 2010, 35:618-626.
• [8]Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA: Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006, 125:301-313.
• [9]Li B, Carey M, Workman JL: The role of chromatin during transcription. Cell 2007, 128:707-719.
• [10]Berger SL: The complex language of chromatin regulation during transcription. Nature 2007, 447:407-412.
• [11]Grewal SIS, Jia S: Heterochromatin revisited. Nat Rev Genet 2007, 8:35-46.
• [12]Weake VM, Workman JL: Inducible gene expression: diverse regulatory mechanisms. Nat Rev Genet 2010, 11:426-437.
• [13]Eissenberg J, Shilatifard A: Leaving a mark: the many footprints of the elongating RNA polymerase II. Curr Opin Genet Dev 2006, 16:184-190.
• [14]Saunders A, Core LJ, Lis JT: Breaking barriers to transcription elongation. Nat Rev Mol Cell Biol 2006, 7:557-567.
• [15]Cosgrove MS, Boeke JD, Wolberger C: Regulated nucleosome mobility and the histone code. Nat Struct Mol Biol 2004, 11:1037-1043.
• [16]Suganuma T, Workman JL: Signals and combinatorial functions of histone modifications. Annu Rev Biochem 2011, 80:473-499.
• [17]Gaszner M, Felsenfeld G: Insulators: exploiting transcriptional and epigenetic mechanisms. Nat Rev Genet 2006, 7:703-713.
• [18]Grewal SI, Elgin SC: Heterochromatin: new possibilities for the inheritance of structure. Curr Opin Genet Dev 2002, 12:178-187.
• [19]Bryant GO, Prabhu V, Floer M, Wang X, Spagna D, Schreiber D, Ptashne M: Activator control of nucleosome occupancy in activation and repression of transcription. PLoS Biol 2008, 6:2928-2939.
• [20]Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, Wang W, Weng Z, Green RD, Crawford GE, Ren B: Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 2007, 39:311-318.
• [21]Mao C, Brown CR, Falkovskaia E, Dong S, Hrabeta-Robinson E, Wenger L, Boeger H: Quantitative analysis of the transcription control mechanism. Mol Syst Biol 2010, 6:431.
• [22]Kim HD, O’Shea EK: A quantitative model of transcription factor-activated gene expression. Nat Struct Mol Biol 2008, 15:1192-1198.
• [23]Hager GL, McNally JG, Misteli T: Transcription dynamics. Mol Cell 2009, 35:741-753.
• [24]Raj A, Peskin CS, Tranchina D, Vargas DY, Tyagi S: Stochastic mRNA synthesis in mammalian cells. PLoS Biol 2006, 4:e309.
• [25]Raj A, van Oudenaarden A: Single-molecule approaches to stochastic gene expression. Annu Rev Biophys 2009, 38:255-270.
• [26]Blake WJ, Balázsi G, Kohanski MA, Isaacs FJ, Murphy KF, Kuang Y, Cantor CR, Walt DR, Collins JJ: Phenotypic consequences of promoter-mediated transcriptional noise. Mol Cell 2006, 24:853-865.
• [27]Chubb JR, Trcek T, Shenoy SM, Singer RH: Transcriptional pulsing of a developmental gene. Curr Biol 2006, 16:1018-1025.
• [28]Raser JM, O’Shea EK: Noise in gene expression: origins, consequences, and control. Science 2005, 309:2010-2013.
• [29]Mogno I, Vallania F, Mitra RD, Cohen BA: TATA is a modular component of synthetic promoters. Genome Res 2010, 20:1391-1397.
• [30]Dodd IB, Micheelsen MA, Sneppen K, Thon G: Theoretical analysis of epigenetic cell memory by nucleosome modification. Cell 2007, 129:813-822.
• [31]Hathaway NA, Bell O, Hodges C, Miller EL, Neel DS, Crabtree GR: Dynamics and memory of heterochromatin in living cells. Cell 2012, 149:1447-1460.
• [32]Hodges C, Crabtree GR: Dynamics of inherently bounded histone modification domains. Proc Natl Acad Sci U S A 2012, 109:13296-13301.
• [33]Satake A, Iwasa Y: A stochastic model of chromatin modification: cell population coding of winter memory in plants. J Theor Biol 2012, 302:6-17.
• [34]Sedighi M, Sengupta A: Epigenetic chromatin silencing: bistability and front propagation. Phys Biol 2007, 4:246-255.
• [35]Angel A, Song J, Dean C, Howard M: A Polycomb-based switch underlying quantitative epigenetic memory. Nature 2011, 476:105-108.
• [36]Mukhopadhyay S, Sengupta AM: The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state. PLoS Comput Biol 2013, 9:e1003121.
• [37]Talbert PB, Henikoff S: Spreading of silent chromatin: inaction at a distance. Nat Rev Genet 2006, 7:793-803.
• [38]Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T: Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001, 410:116-120.
• [39]Canzio D, Chang EY, Shankar S, Kuchenbecker KM, Simon MD, Madhani HD, Narlikar GJ, Al-Sady B: Chromodomain-mediated oligomerization of HP1 suggests a nucleosome-bridging mechanism for heterochromatin assembly. Mol Cell 2011, 41:67-81.
• [40]Gorman J, Greene EC: Visualizing one-dimensional diffusion of proteins along DNA. Nat Struct Mol Biol 2008, 15:768-774.
• [41]Gorman J, Plys AJ, Visnapuu M-L, Alani E, Greene EC: Visualizing one-dimensional diffusion of eukaryotic DNA repair factors along a chromatin lattice. Nat Struct Mol Biol 2010, 17:932-938.
• [42]Stanford NP, Szczelkun MD, Marko JF, Halford SE: One- and three-dimensional pathways for proteins to reach specific DNA sites. EMBO J 2000, 19:6546-6557.
• [43]Maarleveld TR, Olivier BG, Bruggeman FJ: StochPy: a comprehensive, user-friendly tool for simulating stochastic biological processes. PLoS One 2013, 8:e79345.
• [44]Lee W, Tillo D, Bray N, Morse RH, Davis RW, Hughes TR, Nislow C: A high-resolution atlas of nucleosome occupancy in yeast. Nat Genet 2007, 39:1235-1244.
• [45]Lam F, Steger D, O’Shea E: Chromatin decouples promoter threshold from dynamic range. Nature 2008, 453:246-250.
• [46]Blainey PC, Luo G, Kou SC, Mangel WF, Verdine GL, Bagchi B, Xie XS: Nonspecifically bound proteins spin while diffusing along DNA. Nat Struct Mol Biol 2009, 16:1224-1229.
• [47]Tafvizi A, Mirny LA, van Oijen AM: Dancing on DNA: kinetic aspects of search processes on DNA. ChemPhysChem 2011, 12:1481-1489.
• [48]Mirny L, Slutsky M, Wunderlich Z, Tafvizi A, Leith J, Kosmrlj A: How a protein searches for its site on DNA: the mechanism of facilitated diffusion. J Phys A Math Theor 2009, 42:434013.
• [49]Bonnet I, Biebricher A, Porté P-L, Loverdo C, Bénichou O, Voituriez R, Escudé C, Wende W, Pingoud A, Desbiolles P: Sliding and jumping of single EcoRV restriction enzymes on non-cognate DNA. Nucleic Acids Res 2008, 36:4118-4127.
• [50]Maison C, Almouzni G: HP1 and the dynamics of heterochromatin maintenance. Nat Rev Mol Cell Biol 2004, 5:296-304.
• [51]Bohn M, Heermann DW: Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS One 2010, 5:e12218.
• [52]Zee BM, Levin RS, Xu B, LeRoy G, Wingreen NS, Garcia BA: In vivo residue-specific histone methylation dynamics. J Biol Chem 2010, 285:3341-3350.
• [53]Cheutin T, McNairn AJ, Jenuwein T, Gilbert DM, Singh PB, Misteli T: Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science 2003, 299:721-725.
• [54]Gorski SA, Dundr M, Misteli T: The road much traveled: trafficking in the cell nucleus. Curr Opin Cell Biol 2006, 18:284-290.
• [55]Phair R, Scaffidi P, Elbi C, Vecerová J, Dey A, Ozato K, Brown DT, Hager G, Bustin M, Misteli T: Global nature of dynamic protein-chromatin interactions in vivo: three-dimensional genome scanning and dynamic interaction networks of chromatin proteins. Mol Cell Biol 2004, 24:6393-6402.