scholarly journals PICOT binding to chromatin-associated EED negatively regulates cyclin D2 expression by increasing H3K27me3 at the CCND2 gene promoter

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Pinakin Pandya ◽  
Minesh Jethva ◽  
Eitan Rubin ◽  
Ramon Y. Birnbaum ◽  
Alex Braiman ◽  
...  
Keyword(s):  
Target Genes ◽  
Patient Survival ◽  
Leukemia Cell ◽  
Gene Promoter ◽  
Human Tumors ◽  
Polycomb Group ◽  
The Cancer Genome Atlas ◽  
Polycomb Group Protein ◽  
Cyclin D2 ◽  
Human Cancers

Abstract Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3 (Grx3; Glrx3)) is a ubiquitous protein that can interact with the embryonic ectoderm development (EED) protein via each of its two C-terminal PICOT/Grx homology domains. Since EED is a Polycomb-Group protein and a core component of the polycomb repressive complex 2 (PRC2), we tested the involvement of PICOT in the regulation of PRC2-mediated H3 lysine 27 trimethylation (H3K27me3), transcription and translation of selected PRC2 target genes. A fraction of the cellular PICOT protein was found in the nuclei of leukemia cell lines, where it was associated with the chromatin. In addition, PICOT coimmunoprecipitated with chromatin-residing EED derived from Jurkat and COS-7 cell nuclei. PICOT knockdown led to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter. In agreement, PICOT-deficient T cells exhibited a significant increase in CCND2 mRNA and protein expression. Since elevated expression levels of PICOT were reported in several different tumors and correlated in the current studies with decreased transcription and translation of the CCND2 gene, we tested whether this opposite correlation exists in human cancers. Data from the Cancer Genome Atlas (TCGA) database indicated statistically significant negative correlation between PICOT and CCND2 in eight different human tumors where the highest correlation was in lung (p = 8.67E−10) and pancreatic (p = 1.06E−5) adenocarcinoma. Furthermore, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human tumors. The results suggest that PICOT binding to chromatin-associated EED modulates the H3K27me3 level at the CCND2 gene promoter which may be one of the potential mechanisms for regulation of cyclin D2 expression in tumors. These findings also indicate that a low PICOT/CCND2 expression ratio might serve as a good predictor of patient survival in selected human cancers.

scholarly journals SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing

2015 ◽  
Vol 9 (1) ◽  
Author(s):  
Luisa A Wakeling ◽  
Laura J Ions ◽  
Suzanne M Escolme ◽  
Simon J Cockell ◽  
Tianhong Su ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Protein Target ◽  
Group Protein

scholarly journals USP7 Cooperates with SCML2 To Regulate the Activity of PRC1

2015 ◽  
Vol 35 (7) ◽  
pp. 1157-1168 ◽  
Author(s):  
Emilio Lecona ◽  
Varun Narendra ◽  
Danny Reinberg
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Essential Role ◽  
Target Genes ◽  
Polycomb Group ◽  
Histone H2a ◽  
Polycomb Group Protein ◽  
Specific Component ◽  
Group Protein ◽  
The Common ◽  
Polycomb Repressive Complex 1

USP7 is a protein deubiquitinase with an essential role in development. Here, we provide evidence that USP7 regulates the activity of Polycomb repressive complex 1 (PRC1) in coordination with SCML2. There are six versions of PRC1 defined by the association of one of the PCGF homologues (PCGF1 to PCGF6) with the common catalytic subunit RING1B. First, we show that SCML2, a Polycomb group protein that associates with PRC1.2 (containing PCGF2/MEL18) and PRC1.4 (containing PCGF4/BMI1), modulates the localization of USP7 and bridges USP7 with PRC1.4, allowing for the stabilization of BMI1. Chromatin immunoprecipitation (ChIP) experiments demonstrate that USP7 is found at SCML2 and BMI1 target genes. Second, inhibition of USP7 leads to a reduction in the level of ubiquitinated histone H2A (H2Aub), the catalytic product of PRC1 and key for its repressive activity. USP7 regulates the posttranslational status of RING1B and BMI1, a specific component of PRC1.4. Thus, not only does USP7 stabilize PRC1 components, its catalytic activity is also necessary to maintain a functional PRC1, thereby ensuring appropriate levels of repressive H2Aub.

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

2019 ◽  
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.

MES-2, a maternal protein essential for viability of the germline in Caenorhabditis elegans, is homologous to a Drosophila Polycomb group protein

Development ◽  
1998 ◽  
Vol 125 (13) ◽  
pp. 2457-2467 ◽  
Author(s):  
R. Holdeman ◽  
S. Nehrt ◽  
S. Strome
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Target Genes ◽  
Essential Feature ◽  
Primordial Germ Cells ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Maternal Contribution ◽  
Group Protein

A unique and essential feature of germ cells is their immortality. In Caenorhabditis elegans, germline immortality requires the maternal contribution from four genes, mes-2, mes-3, mes-4 and mes-6. We report here that mes-2 encodes a protein similar to the Drosophila Polycomb group protein, Enhancer of zeste, and in the accompanying paper that mes-6 encodes another Polycomb group protein. The Polycomb group is responsible for maintaining proper patterns of expression of the homeotic and other genes in Drosophila. It is thought that Polycomb group proteins form heteromeric complexes and control gene expression by altering chromatin conformation of target genes. As predicted from its similarity to a Polycomb group protein, MES-2 localizes to nuclei. MES-2 is found in germline nuclei in larval and adult worms and in all nuclei in early embryos. By the end of embryogenesis, MES-2 is detected primarily in the two primordial germ cells. The correct distribution of MES-2 requires the wild-type functions of mes-3 and mes-6. We hypothesize that mes-2 encodes a maternal regulator of gene expression in the early germline; its function is essential for normal early development and viability of germ cells.

scholarly journals Mel-18, a Polycomb Group Protein, Regulates Cell Proliferation and Senescence via Transcriptional Repression of Bmi-1 and c-Myc Oncoproteins

2007 ◽  
Vol 18 (2) ◽  
pp. 536-546 ◽  
Author(s):  
Wei-Jian Guo ◽  
Sonal Datta ◽  
Vimla Band ◽  
Goberdhan P. Dimri
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Human Fibroblasts ◽  
Ring Finger ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Down Regulation ◽  
Group Protein ◽  
Bona Fide

Polycomb group (PcG) protein Bmi-1 is an important regulator of cell proliferation. It regulates cellular senescence and proliferation of cells via the transcriptional repression of INK4a/ARF locus and other target genes. Here, we report that Mel-18, a PcG ring finger protein (PCGF) transcriptionally down-regulates Bmi-1. Furthermore, the expression of Bmi-1 and Mel-18 inversely correlates in proliferating and senescent human fibroblasts. Bmi-1 down-regulation by Mel-18 results in accelerated senescence and shortening of the replicative life span in normal human cells. Importantly, using promoter-reporter, chromatin immunoprecipitation, and quantitative real-time primary transcript RT-PCR assays, and an RNA interference approach, we demonstrate that Bmi-1 is a bona fide target of c-Myc oncoprotein. Finally, our data suggest that Mel-18 regulates Bmi-1 expression during senescence via down-regulation of c-Myc. These studies link c-Myc and polycomb function in cell proliferation and senescence.

scholarly journals Retinoic Acid Receptor Isotype Specificity in F9 Teratocarcinoma Stem Cells Results from the Differential Recruitment of Coregulators to Retinoic Acid Response Elements

2007 ◽  
Vol 282 (46) ◽  
pp. 33421-33434 ◽  
Author(s):  
Robert F. Gillespie ◽  
Lorraine J. Gudas
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Response Elements ◽  
Acid Receptor ◽  
Group Protein ◽  
F9 Teratocarcinoma

The retinoic acid receptor (RAR) α, β2, and γ isotypes each regulate specific subsets of target genes in F9 teratocarcinoma stem cells. We used chromatin immunoprecipitation assays to monitor the association of RARγ, retinoic X receptor (RXR) α, and coregulators with the RARβ2, Hoxa1, and Cyp26A1 retinoic acid response elements (RAREs) in F9 wild type and RARα, -β2, and -γ null cells. Additionally we quantitatively monitored expression of the corresponding mRNAs. We demonstrated that the association of RARγ and/or RXRα with a RARE was not sufficient for retinoic acid (RA)-mediated transcription of the corresponding target gene. However, the ability of RARγ and/or RXRα to recruit pCIP (AIB1/ACTR/RAC-3/TRAM-1/SRC-3) and p300 to a RARE did correlate with RA-associated transcription of target mRNAs. Therefore, the specific functions of the RAR isotypes do not manifest at the level of their DNA binding but rather from a differential ability to recruit specific components of the transcriptional machinery. We also demonstrated that RA-mediated displacement of the polycomb group protein SUZ12 from a RARE was inhibited in the absence of RARγ. Thus, transcriptional components of the RAR signaling pathway are specifically required for displacement of SUZ12 from RAREs during RA-mediated differentiation of F9 cells.

scholarly journals Polycomb Factor PHF19 Controls Cell Growth and Differentiation Toward Erythroid Pathway in Chronic Myeloid Leukemia Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Marc García-Montolio ◽  
Cecilia Ballaré ◽  
Enrique Blanco ◽  
Arantxa Gutiérrez ◽  
Sergi Aranda ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Chronic Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Adult Stem Cell ◽  
Erythroid Differentiation ◽  
Polycomb Group ◽  
Leukemia Cells

Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions, such as embryonic development, cell proliferation, and adult stem cell determination. PHD finger protein 19 (PHF19) is an associated factor of Polycomb repressor complex 2 (PRC2), often upregulated in human cancers. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in myeloid leukemia cells. We demonstrated that PHF19 depletion decreases cell proliferation and promotes chronic myeloid leukemia (CML) differentiation. Mechanistically, we have shown how PHF19 regulates the proliferation of CML through a direct regulation of the cell cycle inhibitor p21. Furthermore, we observed that MTF2, a PHF19 homolog, partially compensates for PHF19 depletion in a subset of target genes, instructing specific erythroid differentiation. Taken together, our results show that PHF19 is a key transcriptional regulator for cell fate determination and could be a potential therapeutic target for myeloid leukemia treatment.

scholarly journals Interactions with RNA direct the Polycomb group protein SCML2 to chromatin where it represses target genes

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Roberto Bonasio ◽  
Emilio Lecona ◽  
Varun Narendra ◽  
Philipp Voigt ◽  
Fabio Parisi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Target Genes ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Binding Region ◽  
Group Protein ◽  
Polycomb Repressive Complex 1

Polycomb repressive complex-1 (PRC1) is essential for the epigenetic regulation of gene expression. SCML2 is a mammalian homolog of Drosophila SCM, a Polycomb-group protein that associates with PRC1. In this study, we show that SCML2A, an SCML2 isoform tightly associated to chromatin, contributes to PRC1 localization and also directly enforces repression of certain Polycomb target genes. SCML2A binds to PRC1 via its SPM domain and interacts with ncRNAs through a novel RNA-binding region (RBR). Targeting of SCML2A to chromatin involves the coordinated action of the MBT domains, RNA binding, and interaction with PRC1 through the SPM domain. Deletion of the RBR reduces the occupancy of SCML2A at target genes and overexpression of a mutant SCML2A lacking the RBR causes defects in PRC1 recruitment. These observations point to a role for ncRNAs in regulating SCML2 function and suggest that SCML2 participates in the epigenetic control of transcription directly and in cooperation with PRC1.

Sign in / Sign up

Export Citation Format

Share Document