Trends in Biochemical Sciences
OpinionSpecial Issue: 40 Years of TiBSPolycomb in Transcriptional Phase Transition of Developmental Genes
Section snippets
Expression of Developmental Regulatory Factors: Spatiotemporal Precision and Reversibility
Developmental regulators are generally expressed in a tissue- and stage-specific manner to modulate patterning, differentiation, and proliferation. Morphological and/or functional defects in loss-of-function and gain-of-function mutants suggest that both the repression and activation of these genes are equally crucial for normal development and lifelong tissue homeostasis 1, 2, 3, 4. Notably, this also implies that there could be evolutionarily conserved mechanisms to ensure the developmental
PcG Factors Repress Expression of Developmental Genes
PcG factors were first identified in Drosophila melanogaster as a group of regulators for the Hox (homeotic) cluster genes 15, 16. Remarkably, mutation of these factors caused mis-specification of anterior–posterior segments because of aberrant expression of Hox genes. Since then, a vast number of studies have shown that PcG proteins mediate repressive chromatin structures, at Hox and other target genes, which can be inherited across multiple rounds of cell division [17].
PcG factors mediate
PcG Factors Balance Robust Repression and Activation of Genes
Although PcG factors bind promoter regions of genes, they also mediate interactions between distantly separated genomic regions, which could contribute not only to repression but also activation of genes in a spatiotemporal manner 6, 23, 35, 36, 37, 38. One study used transgenic mice to shows that binding of PcG factors at a CGI in the promoter of human α-globin is regulated by tissue-specific enhancers [39]. In addition, a recent study demonstrated that PcG factors are required to mediate
Activation of Tissue-Specific Enhancers
Activation of tissue-specific enhancers may require two distinct classes of transcription factors (TFs) that cooperate with various epigenetic modifiers to endorse stepwise progression towards enhancer activation (Figure 3, Table 1). The first class is the pioneering TFs, which bind to their target sites; the second class is the inductive TFs, which bring coactivators to target sites for gene activation. In the inactive state, a prospective enhancer sequence, possibly along with methylated
Activation of PcG-Repressed Promoters by Active Enhancers
In general, promoter activation is considered to follow enhancer activation [64]. Repressed promoters of developmental regulator genes are bound by PcG factors and some TrxG factors (i.e., MLL1/2) and consequently marked by H3K27me3, H2AK119u1 and H3K4me3 in ES cells (Figure 4A) 65, 66. This may imply that promoters of developmental regulator genes are already bound by PcG factors and are predisposed to inducible activation by activated enhancers as early as the epiblast stage. Therefore, both
Targeting of PcG Factors by Active Enhancers
To the best of our knowledge, functional and substantial interactions between putative bridging factors and PcG factors during transcriptional regulation have not been reported. However, a functional link between Cohesin complexes and PcG factors has been shown to mediate sister chromatid interactions during Drosophila meiosis [73]. Furthermore, another recent study in Drosophila showed PcG-mediated gene silencing induced by heat shock stress was closely associated with changes in higher-order
Silencing of Active Promoters by PcG Factors
One of the important functions of developmental regulators is to maintain the multipotent and/or premature status of stem or precursor cells. However, since persistent expression of such genes even could affect cellular differentiation 82, 83, they also have to be silenced upon progression of developmental processes or terminal differentiation.
The role of PcG in such processes has been studied in developing neural precursors, in which PcG factors contribute to progressive repression of
Concluding Remarks
In this review, we summarized how PcG factors regulate developmental regulatory genes with an emphasis on their potential roles in promoter–enhancer interactions. The molecular actions of PcG factors at CGI promoters of developmental regulators may be closely linked to enhancer activity particularly during phase transition of transcriptional status. We propose that PcG factor function can be divided into two distinct aspects: robust maintenance of repression, and transition between active and
Acknowledgments
We would like to thank the members of RIKEN-Koseki and KAST laboratories for daily helpful discussions; and Kit-Wan Ma and Jafar Sharif for critical reading of the manuscript. H.K. and T.K. are supported by SIP from the government cabinet office and a Grant-in-Aid from NEXT. T.K. is also funded by the Regional Innovation Program from NEXT.
References (85)
Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts
Cell
(1986)Craniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice
Cell
(1989)- et al.
Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5
Nature
(1991) - et al.
Mutations affecting segment number and polarity in Drosophila
Nature
(1980) - et al.
The role of Hox genes during vertebrate limb development
Curr. Opin. Genet. Dev.
(2007) Polycomb potentiates meis2 activation in midbrain by mediating interaction of the promoter with a tissue-specific enhancer
Dev. Cell
(2014)- et al.
What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory
Nat. Rev. Mol. Cell Biol.
(2014) - et al.
Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes
Curr. Opin. Genet. Dev.
(2002) Locking in stable states of gene expression: transcriptional control during Drosophila development
Curr. Opin. Cell Biol.
(1995)Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene
Genes Dev.
(1994)
Altered Hox expression and segmental identity in Mll-mutant mice
Nature
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Cell
Polycomb complexes repress developmental regulators in murine embryonic stem cells
Nature
Control of developmental regulators by Polycomb in human embryonic stem cells
Cell
A gene complex controlling segmentation in Drosophila
Nature
Polycomblike: a gene that appears to be required for the normal expression of the bithorax and antennapedia gene complexes of Drosophila melanogaster
Genetics
Mechanisms of polycomb gene silencing: knowns and unknowns
Nat. Rev. Mol. Cell Biol.
Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites
Cell
Histone methyltransferase activity of a Drosophila Polycomb group repressor complex
Cell
Role of histone H3 lysine 27 methylation in Polycomb-group silencing
Science
The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans
Mol. Cell. Biol.
Role of histone H2A ubiquitination in Polycomb silencing
Nature
SAM domain polymerization links subnuclear clustering of PRC1 to gene silencing
Dev. Cell
The growth-suppressive function of the polycomb group protein polyhomeotic is mediated by polymerization of its sterile alpha motif (SAM) domain
J. Biol. Chem.
Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity
PLoS Genet.
PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes
Mol. Cell
KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands
Elife
Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation
Mol. Cell
Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes
Nat. Cell Biol.
Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation
Cell
Targeting polycomb to pericentric heterochromatin in embryonic stem cells reveals a role for H2AK119u1 in PRC2 recruitment
Cell Rep.
Histone H2A monoubiquitination promotes histone H3 methylation in Polycomb repression
Nat. Struct. Mol. Biol.
Transcriptional repression by PRC1 in the absence of H2A monoubiquitylation
Genes Dev.
The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development
Genes Dev.
Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila
Cell
Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome
Nat. Genet.
Three-dimensional folding and functional organization principles of the Drosophila genome
Cell
Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization
Cell Stem Cell
Polycomb eviction as a new distant enhancer function
Genes Dev.
Enhancer loops appear stable during development and are associated with paused polymerase
Nature
Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci
Science
Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues
Nat. Genet.
Cited by (21)
Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome
2018, iScienceCitation Excerpt :In the well-established model, PRC2-induced H3K27me3 recruits canonical PRC1, containing CBX as the H3K27me3-binding module. On the other hand, recent studies have reported the existence of variant PRC1s, which lack CBX proteins but bind to a stretch of unmethylated CpG sites and induce H2AK119ub1, independently of PRC2 (Blackledge et al., 2015; Holoch and Margueron, 2017; Kondo et al., 2016). Comprehensive genome sequencing studies identified change-of-function mutations in EZH2, which increase H3K27me3 levels and reduce H3K27me2 levels, in patients with follicular and diffuse large B-cell lymphomas (Morin et al., 2010).
Polycomb group RING finger proteins 3/5 activate transcription via an interaction with the pluripotency factor Tex10 in embryonic stem cells
2017, Journal of Biological ChemistryCitation Excerpt :A canonical PRC1 complex contains one of five different Cbx protein subunits (Cbx2/4/6/7/8) that specifically interact with H3K27me3 via its chromodomain and enable PRC1 recruitment to its target loci (38). Despite the recent advances made in understanding the role of PcG complexes in the epigenetic regulation of gene repression involved in various developmental processes (7, 39), how some of these complexes may interact with the general transcription machinery to contribute to the transcriptional activation remains elusive. In this study, we found that, in contrast to the canonical role of PRC1 in gene repression, Pcgf3/5 predominantly act as transcriptional activators driving expression of a number of genes involved in mesoderm differentiation.
PRC2 Facilitates the Regulatory Topology Required for Poised Enhancer Function during Pluripotent Stem Cell Differentiation
2017, Cell Stem CellCitation Excerpt :Therefore, the PE chromatin signature was proposed to bookmark a limited set of regulatory sequences in pluripotent cells and facilitate their timely and lineage-specific activation once the appropriate differentiation cues become available (Rada-Iglesias et al., 2011). Following their original description, the relevance of PEs was questioned, as they were also found in non-pluripotent cells, where they were proposed to display an inactive rather than poised state or to act as silencers (Bonn et al., 2012; Entrevan et al., 2016; Kondo et al., 2016; Spitz and Furlong, 2012). Most importantly, the functional relevance of PEs for the induction of cognate genes and the execution of somatic differentiation programs remains to be formally demonstrated (Rada-Iglesias et al., 2011; Zentner et al., 2011).
Regulation of Genome Architecture and Function by Polycomb Proteins
2016, Trends in Cell BiologyCitation Excerpt :Activation of the Meis2 gene requires a topological switch mediated by RING1B resulting in an association between the Meis2 gene promoter and an enhancer. In the absence of RING1B, the enhancer can no longer contact the promoter region, resulting in impaired Meis2 gene expression (Box 2) [105]. Here, in contrast to the study of Schoenfelder et al., RING1B is thus required to mediate promoter–enhancer interactions to activate Meis2 gene expression.
The Complex Macromolecular Complex
2016, Trends in Biochemical Sciences
- 4
These authors contributed equally to this work.