Transcriptional repression by Drosophila and mammalian Polycomb group proteins in transfected mammalian cells

The Polycomb group (Pc-G) genes are essential for maintaining the proper spatially restricted expression pattern of the homeotic loci during Drosophila development. The Pc-G proteins appear to function at target loci to maintain a state of transcriptional repression. The murine oncogene bmi-1 has significant homology to the Pc-G gene Posterior sex combs (Psc) and a highly related gene, Suppressor two of zeste [Su(z)2]. We show here that the proteins encoded by bmi-1 and the Pc-G genes Polycomb (Pc) and Psc as well as Su(z)2 mediate repression in mammalian cells when targeted to a promoter by LexA in a cotransfection system. These fusion proteins repress activator function by as much as 30-fold, and the effect on different activation domains is distinct for each Pc-G protein. Repression is observed when the LexA fusion proteins are bound directly adjacent to activator binding sites and also when bound 1,700 bases from the promoter. These data demonstrate that the products of the Pc-G genes can significantly repress activator function on transiently introduced DNA. We suggest that this function contributes to the stable repression of targeted loci during development.

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Histone H2AK119 Mono-Ubiquitination is Essential for Polycomb-Mediated Transcriptional Repression

10.1101/690461 ◽

2019 ◽

Cited By ~ 3

Author(s):

Simone Tamburri ◽

Elisa Lavarone ◽

Daniel Fernández-Pérez ◽

Marika Zanotti ◽

Daria Manganaro ◽

...

Keyword(s):

Cross Talk ◽

Transcriptional Repression ◽

Target Genes ◽

Human Tumors ◽

Polycomb Group ◽

Polycomb Group Proteins ◽

Major Function ◽

Cellular Identity

ABSTRACTThe major function of Polycomb group proteins (PcG) is to maintain transcriptional repression to preserve cellular identity. This is exerted by two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. Both complexes are essential for development and are deregulated in several types of human tumors. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial. Coupling an inducible system with the expression of a fully catalytic inactive RING1B mutant, we demonstrated that H2AK119ub1 deposition is essential to maintain PcG-target genes repressed in ESC. Loss of H2AK119ub1 induced a rapid displacement of PRC2 activity and a loss of H3K27me3 deposition. This affected both PRC2.1 and PRC2.2 variants and further correlated with a strong displacement and destabilization of canonical PRC1. Finally, we find that variant PRC1 forms can sense H2AK119ub1 deposition, which contributes to their stabilization specifically at sites where this modification is highly enriched. Overall our data place H2AK119ub1 deposition as central hub that mount PcG repressive machineries to preserve cell transcriptional identity.

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Polycomb Group and SCF Ubiquitin Ligases Are Found in a Novel BCOR Complex That Is Recruited to BCL6 Targets

Molecular and Cellular Biology ◽

10.1128/mcb.00630-06 ◽

2006 ◽

Vol 26 (18) ◽

pp. 6880-6889 ◽

Cited By ~ 222

Author(s):

Micah D. Gearhart ◽

Connie M. Corcoran ◽

Joseph A. Wamstad ◽

Vivian J. Bardwell

Keyword(s):

Transcriptional Repression ◽

E3 Ligase ◽

Ubiquitin Ligases ◽

Polycomb Group ◽

Fusion Partner ◽

Ubiquitin E3 Ligase ◽

Sex Combs ◽

Demethylase Activity ◽

Jmjc Domain ◽

Mixed Lineage Leukemia Fusion

ABSTRACT The corepressor BCOR potentiates transcriptional repression by the proto-oncoprotein BCL6 and suppresses the transcriptional activity of a common mixed-lineage leukemia fusion partner, AF9. Mutations in human BCOR cause male lethal, X-linked oculofaciocardiodental syndrome. We identified a BCOR complex containing Polycomb group (PcG) and Skp-Cullin-F-box subcomplexes. The PcG proteins include RING1, RYBP, NSPC1, a Posterior Sex Combs homolog, and RNF2, an E3 ligase for the mono-ubiquitylation of H2A. BCOR complex components and mono-ubiquitylated H2A localize to BCL6 targets, indicating that the BCOR complex employs PcG proteins to expand the repertoire of enzymatic activities that can be recruited by BCL6. This also suggests that BCL6 can target PcG proteins to DNA. In addition, the BCOR complex contains components of a second ubiquitin E3 ligase, namely, SKP1 and FBXL10 (JHDM1B). We show that BCOR coimmunoprecipitates isoforms of FBXL10 which contain a JmjC domain that recently has been determined to have histone H3K36 demethylase activity. The recruitment of two distinct classes of E3 ubiquitin ligases and a histone demethylase by BCOR suggests that BCOR uses a unique combination of epigenetic modifications to direct gene silencing.

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Inference and analysis of population-specific fine-scale recombination maps across 26 diverse human populations

Science Advances ◽

10.1126/sciadv.aaw9206 ◽

2019 ◽

Vol 5 (10) ◽

pp. eaaw9206 ◽

Cited By ~ 9

Author(s):

Jeffrey P. Spence ◽

Yun S. Song

Keyword(s):

Binding Sites ◽

Demographic History ◽

Dna Binding Protein ◽

Polycomb Group ◽

Human Populations ◽

Polycomb Group Proteins ◽

Fine Scale ◽

Population Differences ◽

Recombination Rates ◽

History Of

Fine-scale rates of meiotic recombination vary by orders of magnitude across the genome and differ between species and even populations. Studying cross-population differences has been stymied by the confounding effects of demographic history. To address this problem, we developed a demography-aware method to infer fine-scale recombination rates and applied it to 26 diverse human populations, inferring population-specific recombination maps. These maps recapitulate many aspects of the history of these populations including signatures of the trans-Atlantic slave trade and the Iberian colonization of the Americas. We also investigated modulators of the local recombination rate, finding further evidence that Polycomb group proteins and the trimethylation of H3K27 elevate recombination rates. Further differences in the recombination landscape across the genome and between populations are driven by variation in the gene that encodes the DNA binding protein PRDM9, and we quantify the weak effect of meiotic drive acting to remove its binding sites.

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Overlapping Roles of the Methylated DNA-binding Protein MBD1 and Polycomb Group Proteins in Transcriptional Repression ofHOXAGenes and Heterochromatin Foci Formation

Journal of Biological Chemistry ◽

10.1074/jbc.m700011200 ◽

2007 ◽

Vol 282 (22) ◽

pp. 16391-16400 ◽

Cited By ~ 34

Author(s):

Yasuo Sakamoto ◽

Sugiko Watanabe ◽

Takaya Ichimura ◽

Michio Kawasuji ◽

Haruhiko Koseki ◽

...

Keyword(s):

Dna Binding ◽

Transcriptional Repression ◽

Binding Protein ◽

Dna Binding Protein ◽

Polycomb Group ◽

Polycomb Group Proteins ◽

Methylated Dna

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Inference and analysis of population-specific fine-scale recombination maps across 26 diverse human populations

10.1101/532168 ◽

2019 ◽

Cited By ~ 4

Author(s):

Jeffrey P. Spence ◽

Yun S. Song

Keyword(s):

Binding Sites ◽

Demographic History ◽

Dna Binding Protein ◽

Polycomb Group ◽

Human Populations ◽

Polycomb Group Proteins ◽

Fine Scale ◽

Recombination Rates ◽

Confounding Effect ◽

History Of

AbstractFine-scale rates of meiotic recombination vary by several orders of magnitude across the genome, and are known to differ between species and even between populations. Studying the differences in recombination maps across populations has been stymied by the confounding effect of differences in demographic history. To address this problem, we developed a method that infers fine-scale recombination rates while taking demography into account and applied our method to infer population-specific recombination maps for each of 26 diverse human populations. These maps recapitulate many aspects of the history of these populations including signatures of the trans-Atlantic slave trade and the Iberian colonization of the Americas. We also investigated modulators of the local recombination rate, finding an unexpected role for Polycomb-group proteins and the tri-methylation of H3K27 in elevating recombination rates. Further differences in the recombination landscape across the genome and between populations are driven by variation in the gene that encodes the DNA-binding protein PRDM9, and we quantify the weak effect of meiotic drive acting to remove its binding sites.

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Related chromosome binding sites for zeste, suppressors of zeste and Polycomb group proteins in Drosophila and their dependence on Enhancer of zeste function.

The EMBO Journal ◽

10.1002/j.1460-2075.1993.tb05795.x ◽

1993 ◽

Vol 12 (4) ◽

pp. 1513-1522 ◽

Cited By ~ 172

Author(s):

L. Rastelli ◽

C.S. Chan ◽

V. Pirrotta

Keyword(s):

Binding Sites ◽

Polycomb Group ◽

Polycomb Group Proteins ◽

Enhancer Of Zeste ◽

Chromosome Binding

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A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton

Development ◽

10.1242/dev.122.5.1513 ◽

1996 ◽

Vol 122 (5) ◽

pp. 1513-1522 ◽

Cited By ~ 9

Author(s):

T. Akasaka ◽

M. Kanno ◽

R. Balling ◽

M.A. Mieza ◽

M. Taniguchi ◽

...

Keyword(s):

Dna Sequences ◽

Transcriptional Repression ◽

Ectopic Expression ◽

Axial Skeleton ◽

Polycomb Group ◽

Paraxial Mesoderm ◽

Gene Products ◽

Polycomb Group Genes ◽

Sex Combs ◽

Polycomb Group Gene

Segment identity in both invertebrates and vertebrates is conferred by spatially restricted distribution of homeotic gene products. In Drosophila, the expression of Homeobox genes during embryogenesis is initially induced by segmentation gene products and then maintained by Polycomb group and Trithorax group gene products. Polycomb group gene homologs are conserved in vertebrates. Murine mel-18 and closely related bmi-1 are homologous to posterior sex combs and suppressor two of zeste. Mel-18 protein mediates a transcriptional repression via direct binding to specific DNA sequences. To gain further insight into the function of Mel-18, we have inactivated the mel-18 locus by homologous recombination. Mice lacking mel-18 survive to birth and die around 4 weeks after birth after exhibiting strong growth retardation. Similar to the Drosophila posterior sex combs mutant, posterior transformations of the axial skeleton were reproducibly observed in mel-18 mutants. The homeotic transformations were correlated with ectopic expression of Homeobox cluster genes along the anteroposterior axis in the developing paraxial mesoderm. Surprisingly, mel-18-deficient phenotypes are reminiscent of bmi-1 mutants. These results indicate that the vertebrate Polycomb group genes mel-18 and bmi-1, like Drosophila Polycomb group gene products, might play a crucial role in maintaining the silent state of Homeobox gene expression during paraxial mesoderm development.

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Activation and repression by the C-terminal domain of Dorsal

Development ◽

10.1242/dev.128.10.1869 ◽

2001 ◽

Vol 128 (10) ◽

pp. 1869-1879 ◽

Cited By ~ 2

Author(s):

R.D. Flores-Saaib ◽

S. Jia ◽

A.J. Courey

Keyword(s):

Fusion Protein ◽

Concentration Gradient ◽

Binding Sites ◽

Transcriptional Repression ◽

Fusion Proteins ◽

Drosophila Embryo ◽

Terminal Domain ◽

Localization Signal ◽

Pattern Forming ◽

Rel Homology Domain

In the Drosophila embryo, Dorsal, a maternally expressed Rel family transcription factor, regulates dorsoventral pattern formation by activating and repressing zygotically active fate-determining genes. Dorsal is distributed in a ventral-to-dorsal nuclear concentration gradient in the embryo, the formation of which depends upon the spatially regulated inhibition of Dorsal nuclear uptake by Cactus. Using maternally expressed Gal4/Dorsal fusion proteins, we have explored the mechanism of activation and repression by Dorsal. We find that a fusion protein containing the Gal4 DNA-binding domain fused to full-length Dorsal is distributed in a nuclear concentration gradient that is similar to that of endogenous Dorsal, despite the presence of a constitutively active nuclear localization signal in the Gal4 domain. Whether this fusion protein activates or represses reporter genes depends upon the context of the Gal4-binding sites in the reporter. A Gal4/Dorsal fusion protein lacking the conserved Rel homology domain of Dorsal, but containing the non-conserved C-terminal domain also mediates both activation and repression, depending upon Gal4-binding site context. A region close to the C-terminal end of the C-terminal domain has homology to a repression motif in Engrailed - the eh1 motif. Deletion analysis indicates that this region mediates transcriptional repression and binding to Groucho, a co-repressor known to be required for Dorsal-mediated repression. As has previously been shown for repression by Dorsal, we find that activation by Dorsal, in particular by the C-terminal domain, is modulated by the maternal terminal pattern-forming system.

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