scholarly journals BMI1 regulates multiple myeloma-associated macrophage’s pro-myeloma functions

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Danfeng Zhang ◽  
Jingcao Huang ◽  
Fangfang Wang ◽  
Hong Ding ◽  
Yushan Cui ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hedgehog Signaling ◽  
Plasma Cells ◽  
Polycomb Group ◽  
Current Evidence ◽  
Polycomb Group Protein ◽  
Wild Type ◽  
Group Protein ◽  
In Vivo Analysis

AbstractMultiple myeloma (MM) is an aggressive malignancy characterized by terminally differentiated plasma cells accumulation in the bone marrow (BM). MM BM exhibits elevated MΦs (macrophages) numbers relative to healthy BM. Current evidence indicates that MM-MΦs (MM-associated macrophages) have pro-myeloma functions, and BM MM-MΦs numbers negatively correlate with patient survival. Here, we found that BMI1, a polycomb-group protein, modulates the pro-myeloma functions of MM-MΦs, which expressed higher BMI1 levels relative to normal MΦs. In the MM tumor microenvironment, hedgehog signaling in MΦs was activated by MM-derived sonic hedgehog, and BMI1 transcription subsequently activated by c-Myc. Relative to wild-type MM-MΦs, BMI1-KO (BMI1 knockout) MM-MΦs from BM cells of BMI1-KO mice exhibited reduced proliferation and suppressed expression of angiogenic factors. Additionally, BMI1-KO MM-MΦs lost their ability to protect MM cells from chemotherapy-induced cell death. In vivo analysis showed that relative to wild-type MM-MΦs, BMI1-KO MM-MΦs lost their pro-myeloma effects. Together, our data show that BMI1 mediates the pro-myeloma functions of MM-MΦs.

scholarly journals Characterization of Interactions between the Mammalian Polycomb-Group Proteins Enx1/EZH2 and EED Suggests the Existence of Different Mammalian Polycomb-Group Protein Complexes

1998 ◽  
Vol 18 (6) ◽  
pp. 3586-3595 ◽  
Author(s):  
Richard G. A. B. Sewalt ◽  
Johan van der Vlag ◽  
Marco J. Gunster ◽  
Karien M. Hamer ◽  
Jan L. den Blaauwen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Complexes ◽  
Expression Patterns ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Sex Combs ◽  
Group Protein ◽  
Nuclear Domains ◽  
Z Protein

ABSTRACT In Drosophila melanogaster, thePolycomb-group (PcG) andtrithorax-group (trxG) genes have been identified as repressors and activators, respectively, of gene expression. Both groups of genes are required for the stable transmission of gene expression patterns to progeny cells throughout development. Several lines of evidence suggest a functional interaction between the PcG and trxG proteins. For example, genetic evidence indicates that the enhancer of zeste [E(z)] gene can be considered both a PcG and a trxGgene. To better understand the molecular interactions in which the E(z) protein is involved, we performed a two-hybrid screen with Enx1/EZH2, a mammalian homolog of E(z), as the target. We report the identification of the human EED protein, which interacts with Enx1/EZH2. EED is the human homolog ofeed, a murine PcG gene which has extensive homology with the Drosophila PcG gene extra sex combs(esc). Enx1/EZH2 and EED coimmunoprecipitate, indicating that they also interact in vivo. However, Enx1/EZH2 and EED do not coimmunoprecipitate with other human PcG proteins, such as HPC2 and BMI1. Furthermore, unlike HPC2 and BMI1, which colocalize in nuclear domains of U-2 OS osteosarcoma cells, Enx1/EZH2 and EED do not colocalize with HPC2 or BMI1. Our findings indicate that Enx1/EZH2 and EED are members of a class of PcG proteins that is distinct from previously described human PcG proteins.

scholarly journals The iab-7 Polycomb Response Element Maps to a Nucleosome-Free Region of Chromatin and Requires Both GAGA and Pleiohomeotic for Silencing Activity

2001 ◽  
Vol 21 (4) ◽  
pp. 1311-1318 ◽  
Author(s):  
Rakesh K. Mishra ◽  
Jozsef Mihaly ◽  
Stéphane Barges ◽  
Annick Spierer ◽  
François Karch ◽  
...  
Keyword(s):  
Binding Sites ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Gaga Factor ◽  
Response Element ◽  
Polycomb Response Element ◽  
Free Region ◽  
Group Protein

ABSTRACT In the work reported here we have undertaken a functional dissection of a Polycomb response element (PRE) from the iab-7 cis-regulatory domain of the Drosophila melanogasterbithorax complex (BX-C). Previous studies mapped the iab-7PRE to an 860-bp fragment located just distal to the Fab-7boundary. Located within this fragment is an ∼230-bp chromatin-specific nuclease-hypersensitive region called HS3. We have shown that HS3 is capable of functioning as a Polycomb-dependent silencer in vivo, inducing pairing-dependent silencing of amini-white reporter. The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. We show that GAGA and Pho interact with these sequences in vitro and that the consensus binding sites for the two proteins are critical for the silencing activity of theiab-7 PRE in vivo.

The DNA-binding polycomb group protein pleiohomeotic mediates silencing of a Drosophila homeotic gene

Development ◽  
1999 ◽  
Vol 126 (17) ◽  
pp. 3905-3913 ◽  
Author(s):  
C. Fritsch ◽  
J.L. Brown ◽  
J.A. Kassis ◽  
J. Muller
Keyword(s):  
Dna Binding ◽  
Binding Sites ◽  
Point Mutations ◽  
Polycomb Group ◽  
Homeotic Gene ◽  
Homeotic Genes ◽  
Polycomb Group Protein ◽  
Cis Acting ◽  
Group Protein

Polycomb group (PcG) proteins repress homeotic genes in cells where these genes must remain inactive during development. This repression requires cis-acting silencers, also called PcG response elements. Currently, these silencers are ill-defined sequences and it is not known how PcG proteins associate with DNA. Here, we show that the Drosophila PcG protein Pleiohomeotic binds to specific sites in a silencer of the homeotic gene Ultrabithorax. In an Ultrabithorax reporter gene, point mutations in these Pleiohomeotic binding sites abolish PcG repression in vivo. Hence, DNA-bound Pleiohomeotic protein may function in the recruitment of other non-DNA-binding PcG proteins to homeotic gene silencers.

The Polycomb Group Protein Bmi-1 Is Essential for the Growth of Multiple Myeloma Cells

2010 ◽  
Vol 70 (13) ◽  
pp. 5528-5538 ◽  
Author(s):  
Zainab Jagani ◽  
Dmitri Wiederschain ◽  
Alice Loo ◽  
Dan He ◽  
Rebecca Mosher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Myeloma Cells ◽  
Group Protein

The Drosophila Polycomb Group proteins ESC and E(Z) bind directly to each other and co-localize at multiple chromosomal sites

Development ◽  
1998 ◽  
Vol 125 (17) ◽  
pp. 3483-3496 ◽  
Author(s):  
F. Tie ◽  
T. Furuyama ◽  
P.J. Harte
Keyword(s):  
Polycomb Group ◽  
Homeotic Genes ◽  
Polycomb Group Proteins ◽  
Polycomb Group Protein ◽  
Polycomb Group Genes ◽  
Evolutionarily Conserved ◽  
Group Protein ◽  
Essential Prerequisite

The Polycomb Group gene esc encodes an evolutionarily conserved protein required for transcriptional silencing of the homeotic genes. Unlike other Polycomb Group genes, esc is expressed and apparently required only during early embryogenesis, suggesting it is required for the initial establishment of silencing but not for its subsequent maintenance. We present evidence that the ESC protein interacts directly with E(Z), another Polycomb Group protein required for silencing of the homeotic genes. We show that the most highly conserved region of ESC, containing seven WD motifs that are predicted to fold into a beta-propeller structure, mediate its binding to a conserved N-terminal region of E(Z). Mutations in the WD region that perturb ESC silencing function in vivo also perturb binding to E(Z) in vitro. The entire WD region forms a trypsin-resistant structure, like known beta -propeller domains, and mutations that would affect the predicted ESC beta-propeller perturb its trypsin-resistance, while a putative structure-conserving mutation does not. We show by co-immunoprecipitation that ESC and E(Z) are directly associated in vivo and that they also co-localize at many chromosomal binding sites. Since E(Z) is required for binding of other Polycomb Group proteins to chromosomes, these results suggest that formation of an E(Z):ESC complex at Polycomb Response Elements may be an essential prerequisite for the establishment of silencing.

scholarly journals SUMOylation of the polycomb group protein L3MBTL2 facilitates repression of its target genes

2013 ◽  
Vol 42 (5) ◽  
pp. 3044-3058 ◽  
Author(s):  
Christina Stielow ◽  
Bastian Stielow ◽  
Florian Finkernagel ◽  
Maren Scharfe ◽  
Michael Jarek ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Genes ◽  
Polycomb Group ◽  
Hek293 Cells ◽  
Polycomb Group Protein ◽  
Wild Type ◽  
C Terminus ◽  
Lysine Residues ◽  
Group Protein

Abstract Lethal(3) malignant brain tumour like 2 (L3MBTL2) is an integral component of the polycomb repressive complex 1.6 (PRC1.6) and has been implicated in transcriptional repression and chromatin compaction. Here, we show that L3MBTL2 is modified by SUMO2/3 at lysine residues 675 and 700 close to the C-terminus. SUMOylation of L3MBTL2 neither affected its repressive activity in reporter gene assays nor it’s binding to histone tails in vitro. In order to analyse whether SUMOylation affects binding of L3MBTL2 to chromatin, we performed ChIP-Seq analysis with chromatin of wild-type HEK293 cells and with chromatin of HEK293 cells stably expressing either FLAG-tagged SUMOylation-competent or SUMOylation-defective L3MBTL2. Wild-type FLAG-L3MBTL2 and the SUMOylation-defective FLAG-L3MBTL2 K675/700R mutant essentially occupied the same sites as endogenous L3MBTL2 suggesting that SUMOylation of L3MBTL2 does not affect chromatin binding. However, a subset of L3MBTL2-target genes, particularly those with low L3MBTL2 occupancy including pro-inflammatory genes, was de-repressed in cells expressing the FLAG-L3MBTL2 K675/700R mutant. Finally, we provide evidence that SUMOylation of L3MBTL2 facilitates repression of these PRC1.6-target genes by balancing the local H2Aub1 levels established by the ubiquitinating enzyme RING2 and the de-ubiquitinating PR–DUB complex.

scholarly journals SUMO modification is required for in vivo Hox gene regulation by the Caenorhabditis elegans Polycomb group protein SOP-2

2004 ◽  
Vol 36 (5) ◽  
pp. 507-511 ◽  
Author(s):  
Hong Zhang ◽  
Gromoslaw A Smolen ◽  
Rachel Palmer ◽  
Andrea Christoforou ◽  
Sander van den Heuvel ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Caenorhabditis Elegans ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Hox Gene ◽  
Sumo Modification ◽  
Group Protein

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 Global changes of H3K27me3 domains and Polycomb group protein distribution in the absence of recruiters Spps or Pho

2018 ◽  
Vol 115 (8) ◽  
pp. E1839-E1848 ◽  
Author(s):  
J. Lesley Brown ◽  
Ming-an Sun ◽  
Judith A. Kassis
Keyword(s):  
Binding Sites ◽  
Target Genes ◽  
Polycomb Group ◽  
Global Changes ◽  
Polycomb Group Protein ◽  
Protein Distribution ◽  
Wild Type ◽  
Group Protein ◽  
Polycomb Response Elements ◽  
Active Genes

Polycomb group (PcG) proteins maintain the silenced state of key developmental genes in animals, but how these proteins are recruited to specific regions of the genome is still poorly understood. In Drosophila, PcG proteins are recruited to Polycomb response elements (PREs) that include combinations of sites for sequence specific DNA binding “PcG recruiters,” including Pho, Cg, and Spps. To understand their roles in PcG recruitment, we compared Pho-, Cg-, and Spps-binding sites against H3K27me3 and key PcG proteins by ChIP-seq in wild-type and mutant third instar larvae. H3K27me3 in canonical Polycomb domains is decreased after the reduction of any recruiter. Reduction of Spps and Pho, but not Cg, causes the redistribution of H3K27me3 to heterochromatin. Regions with dramatically depleted H3K27me3 after Spps knockout are usually accompanied by decreased Pho binding, suggesting their cooperative binding. PcG recruiters, the PRC2 component E(z), and the PRC1 components Psc and Ph cobind thousands of active genes outside of H3K27me3 domains. This study demonstrates the importance of distinct PcG recruiters for the establishment of unique Polycomb domains. Different PcG recruiters can act both cooperatively and independently at specific PcG target genes, highlighting the complexity and diversity of PcG recruitment mechanisms.

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