scholarly journals Visualization of PRC2-Dinucleosome Interactions Leading to Epigenetic Repression

2018 ◽  
Author(s):  
Simon Poepsel ◽  
Vignesh Kasinath ◽  
Eva Nogales
Keyword(s):  
Epigenetic Regulation ◽  
Protein Complexes ◽  
Histone H3 ◽  
Gene Repression ◽  
Dna Interactions ◽  
Heterochromatin Formation ◽  
Polycomb Repressive Complex 2 ◽  
Nucleosomal Dna ◽  
Epigenetic Regulator ◽  
Epigenetic Repression

AbstractEpigenetic regulation is mediated by protein complexes that couple recognition of chromatin marks to activity or recruitment of chromatin-modifying enzymes. Polycomb repressive complex 2 (PRC2), a gene silencer that methylates lysine 27 of histone H3, is stimulated upon recognition of its own catalytic product, and has been shown to be more active on dinucleosomes than H3 tails or single nucleosomes. These properties likely facilitate local H3K27me2/3 spreading causing heterochromatin formation and gene repression. Here, cryo-EM reconstructions of human PRC2 bound to dinucleosomes show how a single PRC2, interacting with nucleosomal DNA, precisely positions the H3 tails to recognize a H3K27me3 mark in one nucleosome and is stimulated to modify a neighboring nucleosome. The geometry of the PRC2-DNA interactions allow PRC2 to tolerate different dinucleosome geometries due to varying lengths of the linker DNA. Our structures are the first to illustrate how an epigenetic regulator engages with a complex chromatin substrate.

scholarly journals TOWARDS UNDERSTANDING THE MECHANISMS OF EPIGENETIC REGULATION: PART 1. AN EVOLUTIONAL INSIGHT INTO PCG-MEDIATED GENE REPRESSION

2008 ◽  
Vol 6 (1) ◽  
pp. 12-19
Author(s):  
Elena M Fedorova ◽  
Alexander V Rodionov
Keyword(s):  
Epigenetic Regulation ◽  
Current Knowledge ◽  
Gene Repression ◽  
Epigenetic Repression ◽  
Insight Into

The evolutionary conserved PcG proteins maintain stable transcriptional epigenetic repression, established earlier by transiently acting regulator proteins. The exact mechanism of PcG-mediated repression is not identified yet, and here we outline existing models of the repression mechanism. We also shortly summarize the current knowledge about PcG proteins and their role in various processes and present an insight into the evolution of PRC1 and PRC2 complexes.

scholarly journals SETDB1 plays an essential role in maintenance of gonocyte survival in pigs

Reproduction ◽  
2017 ◽  
Vol 154 (1) ◽  
pp. 23-34 ◽  
Author(s):  
Tiantian Liu ◽  
Pengfei Zhang ◽  
Tianjiao Li ◽  
Xiaoxu Chen ◽  
Zhenshuo Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Germ Cells ◽  
Theoretical Basis ◽  
Histone H3 ◽  
Embryonic Stem ◽  
Male Germ Cells ◽  
Heterochromatin Formation ◽  
Epigenetic Regulator ◽  
And Function

Histone methyltransferase SETDB1 suppresses gene expression and modulates heterochromatin formation through H3K9me2/3. Previous studies have revealed that SETDB1 catalyzes lysine 9 of histone H3 tri-methylation and plays essential roles in maintaining the survival of embryonic stem cells and spermatogonial stem cells in mice. However, the function of SETDB1 in porcine male germ cells remains unclear. The aim of the present study was to reveal the expression profile and function of SETDB1 in porcine germ cells. SETDB1 expression gradually increased during testis development. SETDB1 was strongly localized in gonocytes. Knockdown of SETDB1 gene expression led to gonocyte apoptosis and a decrease in H3K27me3, but no significant change in H3K9me3. These observations suggested that SETDB1 is a novel epigenetic regulator of porcine male germ cells, and contributes to the maintenance of gonocyte survival in pigs, probably due to the regulation of H3K27me3 rather than H3K9me3. These findings will provide a theoretical basis for the future study of epigenetic regulation of spermatogenesis.

scholarly journals Mimicking the Nucleosomal Context in Peptide-Based Binders of a H3K36me Reader Increases Binding Affinity While Altering the Binding Mode

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4951
Author(s):  
Velten Horn ◽  
Seino A. K. Jongkees ◽  
Hugo van Ingen
Keyword(s):  
Histone Modification ◽  
Binding Affinity ◽  
Histone H3 ◽  
Binding Pocket ◽  
Binding Mode ◽  
Nmr Analysis ◽  
Dna Interactions ◽  
Nucleosomal Dna ◽  
Binding Pockets ◽  
Selection Of

Targeting of proteins in the histone modification machinery has emerged as a promising new direction to fight disease. The search for compounds that inhibit proteins that readout histone modification has led to several new epigenetic drugs, mostly for proteins involved in recognition of acetylated lysines. However, this approach proved to be a challenging task for methyllysine readers, which typically feature shallow binding pockets. Moreover, reader proteins of trimethyllysine K36 on the histone H3 (H3K36me3) not only bind the methyllysine but also the nucleosomal DNA. Here, we sought to find peptide-based binders of H3K36me3 reader PSIP1, which relies on DNA interactions to tightly bind H3K36me3 modified nucleosomes. We designed several peptides that mimic the nucleosomal context of H3K36me3 recognition by including negatively charged Glu-rich regions. Using a detailed NMR analysis, we find that addition of negative charges boosts binding affinity up to 50-fold while decreasing binding to the trimethyllysine binding pocket. Since screening and selection of compounds for reader domains is typically based solely on affinity measurements due to their lack of enzymatic activity, our case highlights the need to carefully control for the binding mode, in particular for the challenging case of H3K36me3 readers.

scholarly journals H3K27me3 is dispensable for early differentiation but required to maintain differentiated cell identity

2020 ◽  
Author(s):  
Sara A. Miller ◽  
Manashree Damle ◽  
Robert E. Kingston
Keyword(s):  
Stem Cells ◽  
Small Molecule ◽  
Normal Development ◽  
Histone H3 ◽  
Embryonic Stem ◽  
Gene Repression ◽  
Cellular Phenotype ◽  
Polycomb Repressive Complex 2 ◽  
Molecule Inhibitor

AbstractPolycomb repressive complex 2 (PRC2) catalyzes trimethylation of histone H3 on lysine 27 and is required for normal development of complex eukaryotes. The requirement for H3K27me3 in various aspects of mammalian differentiation is not clear. Though associated with repressed genes, the modification is not sufficient to induce gene repression, and in some instances is not required. To examine the role of the modification in mammalian differentiation, we blocked trimethylation of H3K27 with both a small molecule inhibitor, GSK343, and by introducing a point mutation into EZH2, the catalytic subunit of PRC2. We found that cells with substantively decreased H3K27 tri-methylation were able to differentiate, which contrasts with EZH2 null cells. Different PRC2 targets had varied requirements for H3K27me3 in repressive regulation with a subset that maintained normal levels of repression in the absence of methylation. The primary cellular phenotype when H3K27 tri-methylation was blocked was an inability of the altered cells to maintain a differentiated state when challenged. This phenotype was determined by H3K27me3 deposition both in embryonic stem cells and in the first four days of differentiation. H3K27 tri-methylation therefore was not necessary for formation of differentiated cell states but was required to maintain a stable differentiated state.

scholarly journals PWWP INTERACTOR OF POLYCOMBS (PWO1) links PcG-mediated gene repression to the nuclear lamina inArabidopsis

2017 ◽  
Author(s):  
Pawel Mikulski ◽  
Mareike L. Hohenstatt ◽  
Sara Farrona ◽  
Cezary Smaczniak ◽  
Kerstin Kaufmann ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Target Genes ◽  
Protein Complexes ◽  
Nuclear Lamina ◽  
Polycomb Group ◽  
Gene Repression ◽  
Polycomb Repressive Complex 2 ◽  
Peripheral Protein ◽  
Wide Range ◽  
Associated Proteins

AbstractPolycomb group (PcG) proteins facilitate chromatin-mediated gene repression through the modification of histone tails in a wide range of eukaryotes, including plants and animals. One of the PcG protein complexes, Polycomb Repressive Complex 2 (PRC2), promotes repressive chromatin formation via tri-methylation of lysine-27 on histone H3 (H3K27me3). The animal PRC2 is implicated in impacting subnuclear distribution of chromatin as its complex components and H3K27me3 are functionally connected with the nuclear lamina (NL) - a peripheral protein mesh that resides underneath the inner nuclear membrane (INM) and consists of lamins and lamina-associated proteins. In contrast to animals, NL in plants has an atypical structure and its association with PRC2-mediated gene repression is largely unknown. Here, we present a connection between lamin-like protein, CROWDED NUCLEI 1 (CRWN1), and a novel PRC2-associated component, PWWP INTERACTOR OF POLYCOMBS 1 (PWO1), inArabidopsis thaliana. We show that PWO1 and CRWN1 proteins associate physically with each other, act in the same pathway to maintain nuclear morphology and control expression of similar set of target genes. Moreover, we demonstrate that PWO1 proteins form speckle-like foci located partially at the subnuclear periphery inNicotiana benthamianaandArabidopsis thaliana. Ultimately, as CRWN1 and PWO1 are plant-specific, our results argue that plants developed an equivalent, rather than homologous, mechanism of linking PRC2-mediated chromatin repression and nuclear lamina.

Epigenetic Regulator Signatures in Regenerative Capacity

2019 ◽  
Vol 14 (7) ◽  
pp. 598-606
Author(s):  
Sarah Albogami
Keyword(s):  
Epigenetic Regulation ◽  
Animal Species ◽  
Current Knowledge ◽  
Regeneration Process ◽  
Body Parts ◽  
Lysine Methylation ◽  
Regenerative Capacity ◽  
Biological Phenomena ◽  
Epigenetic Regulator

Background:: Regeneration is the process by which body parts lost as a result of injury are replaced, as observed in certain animal species. The root of regenerative differences between organisms is still not very well understood; if regeneration merely recycles developmental pathways in the adult form, why can some animals regrow organs whereas others cannot? In the regulation of the regeneration process as well as other biological phenomena, epigenetics plays an essential role. Objective:: This review aims to demonstrate the role of epigenetic regulators in determining regenerative capacity. Results:: In this review, we discuss the basis of regenerative differences between organisms. In addition, we present the current knowledge on the role of epigenetic regulation in regeneration, including DNA methylation, histone modification, lysine methylation, lysine methyltransferases, and the SET1 family. Conclusion:: An improved understanding of the regeneration process and the epigenetic regulation thereof through the study of regeneration in highly regenerative species will help in the field of regenerative medicine in future.

scholarly journals Histone transfer among chaperones

2012 ◽  
Vol 40 (2) ◽  
pp. 357-363 ◽  
Author(s):  
Wallace H. Liu ◽  
Mair E.A. Churchill
Keyword(s):  
Histone H3 ◽  
Histone Chaperone ◽  
Chromatin Assembly ◽  
Histone Chaperones ◽  
Nucleosome Assembly ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
Nucleosomal Dna ◽  
Chaperone Interactions ◽  
Dependent Processes

The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co-ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly.

scholarly journals Association of BMI1 with Polycomb Bodies Is Dynamic and Requires PRC2/EZH2 and the Maintenance DNA Methyltransferase DNMT1

2005 ◽  
Vol 25 (24) ◽  
pp. 11047-11058 ◽  
Author(s):  
Inmaculada Hernández-Muñoz ◽  
Panthea Taghavi ◽  
Coenraad Kuijl ◽  
Jacques Neefjes ◽  
Maarten van Lohuizen
Keyword(s):  
Dna Methyltransferase ◽  
Pericentric Heterochromatin ◽  
Polycomb Group ◽  
Gene Repression ◽  
Kinetic Properties ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Nuclear Structures ◽  
Stable Maintenance ◽  
Polycomb Bodies

ABSTRACT Polycomb group (PcG) proteins are epigenetic chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized. Polycomb repressive complex 2 (PRC2) is thought to be involved in the initiation of gene silencing, whereas Polycomb repressive complex 1 (PRC1) is implicated in the stable maintenance of gene repression. Here, we investigate the kinetic properties of the binding of one of the PRC1 core components, BMI1, with PcG bodies. PcG bodies are unique nuclear structures located on regions of pericentric heterochromatin, found to be the site of accumulation of PcG complexes in different cell lines. We report the presence of at least two kinetically different pools of BMI1, a highly dynamic and a less dynamic fraction, which may reflect BMI1 pools with different binding capacities to these stable heterochromatin domains. Interestingly, PRC2 members EED and EZH2 appear to be essential for BMI1 recruitment to the PcG bodies. Furthermore, we demonstrate that the maintenance DNA methyltransferase DNMT1 is necessary for proper PcG body assembly independent of DNMT-associated histone deacetylase activity. Together, these results provide new insights in the mechanism for regulation of chromatin silencing by PcG proteins and suggest a highly regulated recruitment of PRC1 to chromatin.

scholarly journals The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis

2004 ◽  
Vol 165 (6) ◽  
pp. 759-765 ◽  
Author(s):  
Creighton T. Tuzon ◽  
Britta Borgstrom ◽  
Dietmar Weilguny ◽  
Richard Egel ◽  
Julia Promisel Cooper ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Mating Type ◽  
Sexual Differentiation ◽  
Histone H3 ◽  
Heterochromatin Protein ◽  
Type Locus ◽  
Heterochromatin Formation ◽  
Mating Type Locus ◽  
Telomere Protein ◽  
Chromosome Movements

Telomeres share the ability to silence nearby transcription with heterochromatin, but the requirement of heterochromatin proteins for most telomere functions is unknown. The fission yeast Rik1 protein is required for heterochromatin formation at centromeres and the mating-type locus, as it recruits the Clr4 histone methyltransferase, whose modification of histone H3 triggers binding by Swi6, a conserved protein involved in spreading of heterochromatin. Here, we demonstrate that Rik1 and Clr4, but not Swi6, are required along with the telomere protein Taz1 for crucial chromosome movements during meiosis. However, Rik1 is dispensable for the protective roles of telomeres in preventing chromosome end-fusion. Thus, a Swi6-independent heterochromatin function distinct from that at centromeres and the mating-type locus operates at telomeres during sexual differentiation.

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