Cooperativity, specificity, and evolutionary stability of Polycomb targeting in Drosophila.

Metazoan genomes are partitioned into modular chromosomal domains containing active or repressive chromatin. In flies, Polycomb group (PcG) response elements (PREs) recruit PHO and other DNA-binding factors and act as nucleation sites for the formation of Polycomb repressive domains. The sequence specificity of PREs is not well understood. Here, we use comparative epigenomics and transgenic assays to show that Drosophila domain organization and PRE specification are evolutionarily conserved despite significant cis-element divergence within Polycomb domains, whereas cis-element evolution is strongly correlated with transcription factor binding divergence outside of Polycomb domains. Cooperative interactions of PcG complexes and their recruiting factor PHO stabilize PHO recruitment to low-specificity sequences. Consistently, PHO recruitment to sites within Polycomb domains is stabilized by PRC1. These data suggest that cooperative rather than hierarchical interactions among low-affinity sequences, DNA-binding factors, and the Polycomb machinery are giving rise to specific and strongly conserved 3D structures in Drosophila.

[1]  Siqian Feng,et al.  Loss of the Polycomb group gene polyhomeotic induces non‐autonomous cell overproliferation , 2011, EMBO reports.

[2]  Jianpeng Ma,et al.  Genome-wide polycomb target gene prediction in Drosophila melanogaster , 2012, Nucleic acids research.

[3]  Amos Tanay,et al.  Inferring divergence of context-dependent substitution rates in Drosophila genomes with applications to comparative genomics. , 2012, Molecular biology and evolution.

[4]  K. White,et al.  Evolution of H3K27me3-marked chromatin is linked to gene expression evolution and to patterns of gene duplication and diversification , 2014, Genome research.

[5]  Giacomo Cavalli,et al.  Polycomb group proteins: repression in 3D. , 2011, Trends in genetics : TIG.

[6]  A. Tanay,et al.  Drosophila Functional Elements Are Embedded in Structurally Constrained Sequences , 2013, PLoS genetics.

[7]  I. Duncan.  Polycomblike: a gene that appears to be required for the normal expression of the bithorax and antennapedia gene complexes of Drosophila melanogaster. , 1982, Genetics.

[8]  O. Cuvier,et al.  Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1 , 2005, Nature.

[9]  J. Zeitlinger,et al.  High conservation of transcription factor binding and evidence for combinatorial regulation across six Drosophila species , 2011, Nature Genetics.

[10]  N. Brockdorff,et al.  Variant PRC1 Complex-Dependent H2A Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation , 2014, Cell.

[11]  Yi Zhang,et al.  Hierarchical recruitment of polycomb group silencing complexes. , 2004, Molecular cell.

[12]  Robert L. Grossman,et al.  A cis-regulatory map of the Drosophila genome , 2011, Nature.

[13]  J. Robert Manak,et al.  Stability and Dynamics of Polycomb Target Sites in Drosophila Development , 2008, PLoS genetics.

[14]  Jürg Müller,et al.  Polycomb response elements and targeting of Polycomb group proteins in Drosophila. , 2006, Current opinion in genetics & development.

[15]  Bradley E. Bernstein,et al.  GC-Rich Sequence Elements Recruit PRC2 in Mammalian ES Cells , 2010, PLoS genetics.

[16]  N. Bonini,et al.  Transcription factor YY1 functions as a PcG protein in vivo , 2003, The EMBO journal.

[17]  M. Whiteley,et al.  The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1. , 1998, Molecular cell.

[18]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[19]  Giacomo Cavalli,et al.  Polycomb silencing: from linear chromatin domains to 3D chromosome folding. , 2014, Current opinion in genetics & development.

[20]  Malgorzata Schelder,et al.  A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. , 2006, Genes & development.

[21]  Lior Pachter,et al.  Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species , 2010, PLoS biology.

[22]  Michael D. Wilson,et al.  Cooperativity and Rapid Evolution of Cobound Transcription Factors in Closely Related Mammals , 2013, Cell.

[23]  Giacomo Cavalli,et al.  Recruitment of Polycomb group complexes and their role in the dynamic regulation of cell fate choice , 2009, Development.

[24]  Renato Paro,et al.  Genome-wide prediction of Polycomb/Trithorax response elements in Drosophila melanogaster. , 2003, Developmental cell.

[25]  E. Rothenberg.  The chromatin landscape and transcription factors in T cell programming. , 2014, Trends in immunology.

[26]  R. Paro,et al.  Evolutionary Plasticity of Polycomb/Trithorax Response Elements in Drosophila Species , 2008, PLoS biology.

[27]  M. Fujioka,et al.  The DNA-binding Polycomb-group protein Pleiohomeotic maintains both active and repressed transcriptional states through a single site , 2008, Development.

[28]  Benjamin Leblanc,et al.  Polycomb-Dependent Regulatory Contacts between Distant Hox Loci in Drosophila , 2011, Cell.

[29]  F. Karch,et al.  Synergistic recognition of an epigenetic DNA element by Pleiohomeotic and a Polycomb core complex. , 2005, Genes & development.

[30]  E. Lewis.  Regulation of the genes of the bithorax complex in Drosophila. , 1985, Cold Spring Harbor symposia on quantitative biology.

[31]  Chiara Lanzuolo,et al.  Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex , 2007, Nature Cell Biology.

[32]  Christopher D. Brown,et al.  A Comprehensive Map of Insulator Elements for the Drosophila Genome , 2010, PLoS genetics.

[33]  Judith K. Brown,et al.  Polycomb group response elements in Drosophila and vertebrates. , 2013, Advances in genetics.

[34]  A. Tanay,et al.  Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome , 2012, Cell.

[35]  R. Paro,et al.  PcG-Mediated Higher-Order Chromatin Structures Modulate Replication Programs at the Drosophila BX-C , 2013, PLoS genetics.

[36]  E. Birney,et al.  A Transcription Factor Collective Defines Cardiac Cell Fate and Reflects Lineage History , 2012, Cell.

[37]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[38]  N. Negre,et al.  PRE-mediated bypass of two Su(Hw) insulators targets PcG proteins to a downstream promoter. , 2006, Developmental cell.

[39]  A. Heger,et al.  Targeting Polycomb to Pericentric Heterochromatin in Embryonic Stem Cells Reveals a Role for H2AK119u1 in PRC2 Recruitment , 2014, Cell reports.

[40]  Thomas Fiedler,et al.  jPREdictor: a versatile tool for the prediction of cis-regulatory elements , 2006, Nucleic Acids Res..

[41]  Y. Schwartz,et al.  Combinatorial Interactions Are Required for the Efficient Recruitment of Pho Repressive Complex (PhoRC) to Polycomb Response Elements , 2014, PLoS genetics.

[42]  Amos Tanay,et al.  Functional Anatomy of Polycomb and Trithorax Chromatin Landscapes in Drosophila Embryos , 2009, PLoS biology.