scholarly journals Impact of Genome Architecture Upon the Functional Activation and Repression of Hox Regulatory Landscapes

2019 ◽  
Author(s):  
Eddie Rodríguez-Carballo ◽  
Lucille Lopez-Delisle ◽  
Nayuta Yakushiji-Kaminatsui ◽  
Asier Ullate-Agote ◽  
Denis Duboule
Keyword(s):  
Gene Cluster ◽  
Spatial Organization ◽  
Target Genes ◽  
Polycomb Group ◽  
Chromatin Domain ◽  
Regulatory Sequences ◽  
Distal Limb ◽  
Polycomb Repressive Complex 2 ◽  
Enhancer Sequences ◽  
Regulatory Landscapes

BackgroundThe spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains are largely determined by bound CTCF molecules and often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases such domains may act as coherent regulatory units, with a global on or off state.ResultsBy using the HoxD gene cluster as a paradigm, we investigated the effect of large genomic rearrangements affecting the two TADs flanking this locus, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers initially positioned in either TADs globally occurred as when both TADs are intact. We also show that the timely implementation of distal limb enhancers depends on whether or not target genes had previously responded to proximal enhancers, due to the presence or absence of H3K27me3 marks.ConclusionsFrom this work, we conclude that antagonistic limb proximal and distal enhancers can exert their specificities when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing and thus prolonged its activity in time. Since Polycomb group proteins are mainly recruited at the Hox gene cluster, our results suggest that Polycomb Repressive Complex 2 (PRC2) can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.

scholarly journals RYBP stimulates PRC1 to shape chromatin-based communication between Polycomb repressive complexes

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Nathan R Rose ◽  
Hamish W King ◽  
Neil P Blackledge ◽  
Nadezda A Fursova ◽  
Katherine JI Ember ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Histone Modification ◽  
Target Genes ◽  
Embryonic Stem ◽  
Polycomb Group ◽  
Chromatin Domain ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Ubiquitin Ligase Activity ◽  
Inappropriate Gene Expression

Polycomb group (PcG) proteins function as chromatin-based transcriptional repressors that are essential for normal gene regulation during development. However, how these systems function to achieve transcriptional regulation remains very poorly understood. Here, we discover that the histone H2AK119 E3 ubiquitin ligase activity of Polycomb repressive complex 1 (PRC1) is defined by the composition of its catalytic subunits and is highly regulated by RYBP/YAF2-dependent stimulation. In mouse embryonic stem cells, RYBP plays a central role in shaping H2AK119 mono-ubiquitylation at PcG targets and underpins an activity-based communication between PRC1 and Polycomb repressive complex 2 (PRC2) which is required for normal histone H3 lysine 27 trimethylation (H3K27me3). Without normal histone modification-dependent communication between PRC1 and PRC2, repressive Polycomb chromatin domains can erode, rendering target genes susceptible to inappropriate gene expression signals. This suggests that activity-based communication and histone modification-dependent thresholds create a localized form of epigenetic memory required for normal PcG chromatin domain function in gene regulation.

scholarly journals PWO1 interacts with PcG proteins and histones to regulate Arabidopsis flowering and development

2017 ◽  
Author(s):  
Mareike L. Hohenstatt ◽  
Pawel Mikulski ◽  
Olga Komarynets ◽  
Constanze Klose ◽  
Ina Kycia ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Target Genes ◽  
Polycomb Group ◽  
Nuclear Speckles ◽  
Triple Mutant ◽  
Pwwp Domain ◽  
Histone Methyltransferases ◽  
Polycomb Repressive Complex 2 ◽  
Epigenetic Gene Regulation

AbstractPolycomb-group (PcG) proteins mediate epigenetic gene regulation by setting H3K27me3 via Polycomb Repressive Complex 2 (PRC2). In plants, it is largely unclear how PcG proteins are recruited to their target genes.Here, we identified the PWWP-DOMAIN INTERACTOR OF POLYCOMBS1 (PWO1) protein which interacts with all three Arabidopsis PRC2 histone methyltransferases and is required for keeping full H3 occupancy at several Arabidopsis genes. PWO1 localizes and recruits CLF to nuclear speckles in tobacco nuclei, suggesting a role in spatial organization of PcG regulation. PWO1 belongs to a gene family with three members acting redundantly: pwo1 pwo2 pwo3 triple mutants are seedling lethal and show shoot and root meristem arrest, while pwo1 single mutants are early flowering. Interestingly, PWO1’s PWWP domain confers binding to histones, which is reduced by a point mutation in a highly conserved residue of this domain and blocked by phosphorylation of H3S28. PWO1 carrying this mutation is not able to fully complement the pwo1 pwo2 pwo3 triple mutant, indicating the requirement of this domain for PWO1 in vivo activity. Thus, the PWO family may present a novel class of histone readers which are involved in recruiting PcG proteins to subnuclear domains and in promoting Arabidopsis development.

scholarly journals Polycomb-group recruitment to a Drosophila target gene is the default state that is inhibited by a transcriptional activator

2021 ◽  
Vol 7 (29) ◽  
pp. eabg1556
Author(s):  
Elnaz Ghotbi ◽  
Piao Ye ◽  
Taylor Ervin ◽  
Anni Kum ◽  
Judith Benes ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Gene ◽  
Target Genes ◽  
De Novo ◽  
Polycomb Group ◽  
Polycomb Repressive Complex 2 ◽  
Repressive Chromatin ◽  
Group Recruitment ◽  
Default State ◽  
Present Experimental Evidence

Polycomb-group (PcG) proteins are epigenetic regulators that maintain the transcriptional repression of target genes following their initial repression by transcription factors. PcG target genes are repressed in some cells, but active in others. Therefore, a mechanism must exist by which PcG proteins distinguish between the repressed and active states and only assemble repressive chromatin environments at target genes that are repressed. Here, we present experimental evidence that the repressed state of a Drosophila PcG target gene, giant (gt), is not identified by the presence of a repressor. Rather, de novo establishment of PcG-mediated silencing at gt is the default state that is prevented by the presence of an activator or coactivator, which may inhibit the catalytic activity of Polycomb-repressive complex 2 (PRC2).

scholarly journals Defining the Boundaries of Polycomb Domains in Drosophila

Genetics ◽  
2020 ◽  
Vol 216 (3) ◽  
pp. 689-700
Author(s):  
Sandip De ◽  
Natalie D. Gehred ◽  
Miki Fujioka ◽  
Fountane W. Chan ◽  
James B. Jaynes ◽  
...  
Keyword(s):  
Target Genes ◽  
Additional Data ◽  
Transcription Unit ◽  
Polycomb Group ◽  
Transcriptional Repressors ◽  
Enhancer Activity ◽  
Transcriptional Terminator ◽  
Polycomb Repressive Complex 2 ◽  
Active Transcription ◽  
Polycomb Response Elements

Polycomb group (PcG) proteins are an important group of transcriptional repressors that act by modifying chromatin. PcG target genes are covered by the repressive chromatin mark H3K27me3. Polycomb repressive complex 2 (PRC2) is a multiprotein complex that is responsible for generating H3K27me3. In Drosophila, PRC2 is recruited by Polycomb Response Elements (PREs) and then trimethylates flanking nucleosomes, spreading the H3K27me3 mark over large regions of the genome, the “Polycomb domains.” What defines the boundary of a Polycomb domain? There is experimental evidence that insulators, PolII, and active transcription can all form the boundaries of Polycomb domains. Here we divide the boundaries of larval Polycomb domains into six different categories. In one category, genes are transcribed toward the Polycomb domain, where active transcription is thought to stop the spreading of H3K27me3. In agreement with this, we show that introducing a transcriptional terminator into such a transcription unit causes an extension of the Polycomb domain. Additional data suggest that active transcription of a boundary gene may restrict the range of enhancer activity of a Polycomb-regulated gene.

scholarly journals The polycomb group protein complex of Drosophila melanogaster has different compositions at different target genes.

1997 ◽  
Vol 17 (12) ◽  
pp. 6773-6783 ◽  
Author(s):  
H Strutt ◽  
R Paro
Keyword(s):  
Protein Complex ◽  
Target Genes ◽  
Regulatory Elements ◽  
Polycomb Group ◽  
Regulatory Sequences ◽  
Polycomb Group Protein ◽  
Polycomb Group Genes ◽  
Sex Combs ◽  
Group Protein

In Drosophila the Polycomb group genes are required for the long-term maintenance of the repressed state of many developmental regulatory genes. Their gene products are thought to function in a common multimeric complex that associates with Polycomb group response elements (PREs) in target genes and regulates higher-order chromatin structure. We show that the chromodomain of Polycomb is necessary for protein-protein interactions within a Polycomb-Polyhomeotic complex. In addition, Posterior Sex Combs protein coimmunoprecipitates Polycomb and Polyhomeotic, indicating that they are members of a common multimeric protein complex. Immunoprecipitation experiments using in vivo cross-linked chromatin indicate that these three Polycomb group proteins are associated with identical regulatory elements of the selector gene engrailed in tissue culture cells. Polycomb, Polyhomeotic, and Posterior Sex Combs are, however, differentially distributed on regulatory sequences of the engrailed-related gene invected. This suggests that there may be multiple different Polycomb group protein complexes which function at different target sites. Furthermore, Polyhomeotic and Posterior Sex Combs are also associated with expressed genes. Polyhomeotic and Posterior Sex Combs may participate in a more general transcriptional mechanism that causes modulated gene repression, whereas the inclusion of Polycomb protein in the complex at PREs leads to stable silencing.

scholarly journals Chromatin topology and the timing of enhancer function at the hoxd locus

2020 ◽  
Author(s):  
Eddie Rodríguez-Carballo ◽  
Lucille Lopez-Delisle ◽  
Andréa Willemin ◽  
Leonardo Beccari ◽  
Sandra Gitto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Gene Activation ◽  
Ctcf Binding ◽  
Regulatory Sequences ◽  
Promoter Recognition ◽  
Key Factor ◽  
Natural Target ◽  
Enhancer Sequences ◽  
The Impact

ABSTRACTThe HoxD gene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different sub-groups of Hoxd genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate from two distinct TADs flanking HoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory sub-modules. To understand the importance of this particular regulatory topology to control Hoxd gene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation of Hoxd genes illustrate the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts was eventually resumed, showing that the presence of enhancers sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavourable orientation of CTCF sites.SIGNIFICANCE STATEMENTMany genes important for vertebrate development are surrounded by series of remote enhancer sequences. Such regulatory landscapes and their target genes are usually located within the same chromatin domains, which appears to constrain the action of these regulatory sequences and hence to facilitate enhancer-promoter recognition and gene expression. We used the HoxD locus to assess the impact of modifying the regulatory topology upon gene activation in space and time. A series of chromosomal re-arrangements involving deletions and inversions reveals that the enhancer topology plays a role in the timing of gene activation. However, gene expression was often recovered, subsequently, illustrating the intrinsic capacity of some enhancers to find their target promoters despite an apparently adverse chromatin topology.

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.

scholarly journals Modeling Enhancer-Promoter Interactions with Attention-Based Neural Networks

2017 ◽  
Author(s):  
Weiguang Mao ◽  
Dennis Kostka ◽  
Maria Chikina
Keyword(s):  
Dna Sequences ◽  
Target Genes ◽  
Expression Patterns ◽  
Regulatory Sequences ◽  
Learning Approaches ◽  
Interaction Prediction ◽  
Genome Wide ◽  
Gene Regulatory ◽  
Enhancer Function ◽  
Enhancer Sequences

AbstractBackgroundGene regulatory sequences play critical roles in ensuring tightly controlled RNA expression patterns that are essential in a large variety of biological processes. Specifically, enhancer sequences drive expression of their target genes, and the availability of genome-wide maps of enhancer-promoter interactions has opened up the possibility to use machine learning approaches to extract and interpret features that define these interactions in different biological contexts.MethodsInspired by machine translation models we develop an attention-based neural network model, EPIANN, to predict enhancer-promoter interactions based on DNA sequences. Codes and data are available at https://github.com/wgmao/EPIANN.ResultsOur approach accurately predicts enhancer-promoter interactions across six cell lines. In addition, our method generates pairwise attention scores at the sequence level, which specify how short regions in the enhancer and promoter pair-up to drive the interaction prediction. This allows us to identify over-represented transcription factors (TF) binding sites and TF-pair interactions in the context of enhancer function.

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