A theoretical model of Polycomb/Trithorax action unites stable epigenetic memory and dynamic regulation.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Epigenomics* ; Models, Theoretical*; Chromosomal Proteins, Non-Histone/*genetics ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*genetics ; Gene Expression Regulation, Developmental/*genetics ; Polycomb Repressive Complex 1/*genetics; Animals ; Cell Division ; Chromosomal Proteins, Non-Histone/metabolism ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster/physiology ; Epigenesis, Genetic ; Female ; Gene Silencing ; Polycomb Repressive Complex 1/metabolism ; Polycomb-Group Proteins/metabolism ; Promoter Regions, Genetic ; Response Elements

Polycomb and Trithorax group proteins maintain stable epigenetic memory of gene expression states for some genes, but many targets show highly dynamic regulation. Here we combine experiment and theory to examine the mechanistic basis of these different modes of regulation. We present a mathematical model comprising a Polycomb/Trithorax response element (PRE/TRE) coupled to a promoter and including Drosophila developmental timing. The model accurately recapitulates published studies of PRE/TRE mediated epigenetic memory of both silencing and activation. With minimal parameter changes, the same model can also recapitulate experimental data for a different PRE/TRE that allows dynamic regulation of its target gene. The model predicts that both cell cycle length and PRE/TRE identity are critical for determining whether the system gives stable memory or dynamic regulation. Our work provides a simple unifying framework for a rich repertoire of PRE/TRE functions, and thus provides insights into  genome-wide Polycomb/Trithorax regulation.

Ptashne, M. & Gann, A. Genes and Signals. (Cold Spring Harbor Laboratory Press, 2002).
Simon, J., Chiang, A., Bender, W., Shimell, M. J. & O’Connor, M. Elements of the Drosophila bithorax complex that mediate repression by Polycomb group products. Dev. Biol. 158, 131–144 (1993). (PMID: 8101171)
Chan, C. S., Rastelli, L. & Pirrotta, V. A Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression. EMBO J. 13, 2553–2564 (1994). (PMID: 7912192395129)
Steffen, P. A. & Ringrose, L. What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. Nat. Rev. Mol. Cell Biol. 15, 340–356 (2014). (PMID: 24755934)
Woo, C. J., Kharchenko, P. V., Daheron, L., Park, P. J. & Kingston, R. E. A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell 140, 99–110 (2010). (PMID: 200857053324942)
Cavalli, G. & Paro, R. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93, 505–518 (1998). (PMID: 9604927)
Hagstrom, K., Muller, M. & Schedl, P. A Polycomb and GAGA dependent silencer adjoins the Fab-7 boundary in the Drosophila bithorax complex. Genetics 146, 1365–1380 (1997). (PMID: 92586801208081)
Busturia, A., Wightman, C. D. & Sakonju, S. A silencer is required for maintenance of transcriptional repression throughout Drosophila development. Development 124, 4343–4350 (1997). (PMID: 9334282)
Americo, J. et al. A complex array of DNA-binding proteins required for pairing-sensitive silencing by a polycomb group response element from the Drosophila engrailed gene. Genetics 160, 1561–1571 (2002). (PMID: 119733101462036)
Rank, G., Prestel, M. & Paro, R. Transcription through intergenic chromosomal memory elements of the Drosophila bithorax complex correlates with an epigenetic switch. Mol. Cell Biol. 22, 8026–8034 (2002). (PMID: 12391168134728)
Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev. Genet 38, 413–443 (2004). (PMID: 15568982)
Ringrose, L., Rehmsmeier, M., Dura, J. & Paro, R. Genome-wide prediction of Polycomb/Trithorax response elements in Drosophila melanogaster. Dev. Cell 5, 759–771 (2003). (PMID: 14602076)
Ringrose, L. Polycomb comes of age: genome-wide profiling of target sites. Curr. Opin. Cell Biol. 19, 290–297 (2007). (PMID: 17481880)
Oktaba, K. et al. Dynamic regulation by polycomb group protein complexes controls pattern formation and the cell cycle in Drosophila. Dev. Cell 15, 877–889 (2008). (PMID: 18993116)
Schuettengruber, B. et al. Functional anatomy of polycomb and trithorax chromatin landscapes in Drosophila embryos. PLoS Biol. 7, e13 (2009). (PMID: 19143474)
Schwartz, Y. B. et al. Alternative epigenetic chromatin states of polycomb target genes. PLoS Genet. 6, e1000805 (2010). (PMID: 200628002799325)
Maurange, C. & Paro, R. A cellular memory module conveys epigenetic inheritance of hedgehog expression during Drosophila wing imaginal disc development. Genes Dev. 16, 2672–2683 (2002). (PMID: 12381666187463)
Martinez, A. M., Colomb, S., Dejardin, J., Bantignies, F. & Cavalli, G. Polycomb group-dependent Cyclin A repression in Drosophila. Genes Dev. 20, 501–513 (2006). (PMID: 164814771369051)
Perez, L. et al. Enhancer-PRE communication contributes to the expansion of gene expression domains in proliferating primordia. Development 138, 3125–3134 (2011). (PMID: 21715425)
Herzog, V. A. et al. A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element. Nat. Genet. 46, 973–981 (2014). (PMID: 251083844270207)
Dodd, I. B., Micheelsen, M. A., Sneppen, K. & Thon, G. Theoretical analysis of epigenetic cell memory by nucleosome modification. Cell 129, 813–822 (2007). (PMID: 17512413)
Angel, A., Song, J., Dean, C. & Howard, M. A Polycomb-based switch underlying quantitative epigenetic memory. Nature 476, 105–108 (2011). (PMID: 21785438)
Sneppen, K. & Ringrose, L. Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent. Nat. Commun. 10, 2133 (2019). in press. (PMID: 310861776513952)
Kassis, J. A. & Brown, J. L. Polycomb group response elements in Drosophila and vertebrates. Adv. Genet. 81, 83–118 (2013). (PMID: 234197174157523)
Bauer, M., Trupke, J. & Ringrose, L. The quest for mammalian Polycomb response elements: are we there yet? Chromosoma 125, 471–496 (2016). (PMID: 26453572)
Martínez-Balbás, M. A., Dey, A., Rabindran, S. K., Ozato, K. & Wu, C. Displacement of sequence-specific transcription factors from mitotic chromatin. Cell 83, 29–38 (1995). (PMID: 7553870)
Parsons, G. G. & Spencer, C. A. Mitotic repression of RNA polymerase II transcription is accompanied by release of transcription elongation complexes. Mol. Cell. Biol. 17, 5791–5802 (1997). (PMID: 9315637232427)
Spencer, C. A., Kruhlak, M. J., Jenkins, H. L., Sun, X. & Bazett-Jones, D. P. Mitotic transcription repression in vivo in the absence of nucleosomal chromatin condensation. J. Cell Biol. 150, 13–26 (2000). (PMID: 108932522185571)
Alabert, C. et al. Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev. 29, 585–590 (2015). (PMID: 257925964378191)
Blythe, S. A. & Wieschaus, E. F. Coordinating cell cycle remodeling with transcriptional activation at the Drosophila MBT. Curr. Top. Dev. Biol. 113, 113–148 (2015). (PMID: 26358872)
Zerihun, M. B., Vaillant, C. & Jost, D. Effect of replication on epigenetic memory and consequences on gene transcription. Phys. Biol. 12, 026007 (2015). (PMID: 25884278)
Shermoen, A. W., McCleland, M. L. & O’Farrell, P. H. Developmental control of late replication and S phase length. Curr. Biol. 20, 2067–2077 (2010). (PMID: 210744393108027)
Yuan, K. & O’Farrell, P. H. TALE-light imaging reveals maternally guided, H3K9me2/3-independent emergence of functional heterochromatin in Drosophila embryos. Genes Dev. 30, 579–593 (2016). (PMID: 269158204782051)
Li, X. Y., Harrison, M. M., Villalta, J. E., Kaplan, T. & Eisen, M. B. Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition. eLife 3, e03737 (2014). (PMID: 4358338)
Bonnet, J. et al. Quantification of proteins and histone marks in Drosophila embryos reveals stoichiometric relationships impacting chromatin regulation. Dev. Cell 51, 632–644 e636 (2019). (PMID: 31630981)
Williamson, A. & Lehmann, R. Germ cell development in Drosophila. Annu. Rev. cell Dev. Biol. 12, 365–391 (1996). (PMID: 8970731)
Foe, V. E. Mitotic domains reveal early commitment of cells in Drosophila embryos. Development 107, 1–22 (1989). (PMID: 2516798)
Zenk, F. et al. Germ line-inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition. Science 357, 212–216 (2017). (PMID: 28706074)
Bui, Q. T., Zimmerman, J. E., Liu, H., Gray-Board, G. L. & Bonini, N. M. Functional analysis of an eye enhancer of the Drosophila eyes absent gene: differential regulation by eye specification genes. Dev. Biol. 221, 355–364 (2000). (PMID: 10790331)
Kumar, J. P. The molecular circuitry governing retinal determination. Biochim Biophys. Acta 1789, 306–314 (2009). (PMID: 19013263)
Okulski, H., Druck, B., Bhalerao, S. & Ringrose, L. Quantitative analysis of polycomb response elements (PREs) at identical genomic locations distinguishes contributions of PRE sequence and genomic environment. Epigenetics Chromatin 4, 4 (2011). (PMID: 214109563070613)
Berry, S., Dean, C. & Howard, M. Slow chromatin dynamics allow polycomb target genes to filter fluctuations in transcription factor activity. Cell Syst. 4, 445–457 e448 (2017). (PMID: 283427175409831)
Sneppen, K. Models of life: epigenetics, diversity and cycles. Reports on progress in physics. Phys. Soc. 80, 042601 (2017).
Ficz, G., Heintzmann, R. & Arndt-Jovin, D. J. Polycomb group protein complexes exchange rapidly in living Drosophila. Development 132, 3963–3976 (2005). (PMID: 16079157)
Fonseca, J. P. et al. In vivo Polycomb kinetics and mitotic chromatin binding distinguish stem cells from differentiated cells. Genes Dev. 26, 857–871 (2012). (PMID: 225087293337459)
Meshorer, E. et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10, 105–116 (2006). (PMID: 163990821868458)
Perino, M. & Veenstra, G. J. Chromatin control of developmental dynamics and plasticity. Dev. Cell 38, 610–620 (2016). (PMID: 27676434)
Seller, C. A., Cho, C. Y. & O’Farrell, P. H. Rapid embryonic cell cycles defer the establishment of heterochromatin by Eggless/SetDB1 in Drosophila. Genes Dev. 33, 403–417 (2019). (PMID: 308086586446540)
Yang, H. et al. Distinct phases of Polycomb silencing to hold epigenetic memory of cold in Arabidopsis. Science 357, 1142–1145 (2017). (PMID: 28818969)
Kwon, D. et al. Enhancer-promoter communication at the Drosophila engrailed locus. Development 136, 3067–3075 (2009). (PMID: 196751302730364)
Ringrose, L. Noncoding RNAs in Polycomb and Trithorax regulation: a quantitative perspective. Annu Rev. Genet. 51, 385–411 (2017). (PMID: 28934594)
Hug, C. B., Grimaldi, A. G., Kruse, K. & Vaquerizas, J. M. Chromatin architecture emerges during zygotic genome activation independent of transcription. Cell 169, 216–228 e219 (2017). (PMID: 28388407)
Gemkow, M. J., Verveer, P. J. & Arndt-Jovin, D. J. Homologous association of the Bithorax-Complex during embryogenesis: consequences for transvection in Drosophila melanogaster. Development 125, 4541–4552 (1998). (PMID: 9778512)
Kassis, J. A. Unusual properties of regulatory DNA from the Drosophila engrailed gene: three “pairing-sensitive” sites within a 1.6-kb region. Genetics 136, 1025–1038 (1994). (PMID: 80054121205860)
Fauvarque, M. O. & Dura, J. M. polyhomeotic regulatory sequences induce developmental regulator-dependent variegation and targeted P-element insertions in Drosophila. Genes Dev. 7, 1508–1520 (1993). (PMID: 8101825)
Wall, G., Varga-Weisz, P. D., Sandaltzopoulos, R. & Becker, P. B. Chromatin remodeling by GAGA factor and heat shock factor at the hypersensitive Drosophila hsp26 promoter in vitro. EMBO J. 14, 1727–1736 (1995). (PMID: 7737124398266)
Katsani, K. R., Hajibagheri, M. A. & Verrijzer, C. P. Co-operative DNA binding by GAGA transcription factor requires the conserved BTB/POZ domain and reorganizes promoter topology. EMBO J. 18, 698–708 (1999). (PMID: 99274291171162)
Hauenschild, A., Ringrose, L., Altmutter, C., Paro, R. & Rehmsmeier, M. Evolutionary plasticity of polycomb/trithorax response elements in Drosophila species. PLoS Biol. 6, e261 (2008). (PMID: 189594832573935)
Ringrose, L., Ehret, H. & Paro, R. Distinct contributions of histone H3 lysine 9 and 27 methylation to locus-specific stability of polycomb complexes. Mol. Cell 16, 641–653 (2004). (PMID: 15546623)
Rothwell, W. F., Sullivan, W. Fluorescent analysis of Drosophila embryos in Drosophila protocols (eds. Sullivan, W., Ashburner, M. & Scott Hawley, R.) 141–157 (CSHL Press, 2000).
Orlando, V., Jane, E. P., Chinwalla, V., Harte, P. J. & Paro, R. Binding of trithorax and Polycomb proteins to the bithorax complex: dynamic changes during early Drosophila embryogenesis. Embo J. 17, 5141–5150 (1998). (PMID: 97246501170842)
Horton, R. M., Hunt, H. D., Ho, S. N., Pullen, J. K. & Pease, L. R. Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. Gene 77, 61–68 (1989). (PMID: 27444882744488)

BBS/E/J/000PR9773 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/J004588/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/P013511/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council

0 (Chromosomal Proteins, Non-Histone)
0 (DNA-Binding Proteins)
0 (Drosophila Proteins)
0 (Pc protein, Drosophila)
0 (Polycomb-Group Proteins)
0 (trx protein, Drosophila)
EC 2.3.2.27 (Polycomb Repressive Complex 1)

Date Created: 20200923 Date Completed: 20201013 Latest Revision: 20210922

20250114

PMC7508846

10.1038/s41467-020-18507-4

32963223