scholarly journals SALL1 Modulates CBX4 Stability, Nuclear Bodies, and Regulation of Target Genes

2021 ◽  
Vol 9 ◽  
Author(s):  
Immacolata Giordano ◽  
Lucia Pirone ◽  
Veronica Muratore ◽  
Eukene Landaluze ◽  
Coralia Pérez ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Limb Development ◽  
Target Genes ◽  
Nuclear Bodies ◽  
Polycomb Repressive Complex ◽  
Complex Interplay ◽  
Polycomb Bodies ◽  
Polycomb Repressive Complex 1 ◽  
The Relationship

Development is orchestrated through a complex interplay of multiple transcription factors. The comprehension of this interplay will help us to understand developmental processes. Here we analyze the relationship between two key transcription factors: CBX4, a member of the Polycomb Repressive Complex 1 (PRC1), and SALL1, a member of the Spalt-like family with important roles in embryogenesis and limb development. Both proteins localize to nuclear bodies and are modified by the small ubiquitin-like modifier (SUMO). Our results show that CBX4 and SALL1 interact in the nucleoplasm and that increased SALL1 expression reduces ubiquitination of CBX4, enhancing its stability. This is accompanied by an increase in the number and size of CBX4-containing Polycomb bodies, and by a greater repression of CBX4 target genes. Thus, our findings uncover a new way of SALL1-mediated regulation of Polycomb bodies through modulation of CBX4 stability, with consequences in the regulation of its target genes, which could have an impact in cell differentiation and development.

scholarly journals Direct Recruitment of Polycomb Repressive Complex 1 to Chromatin by Core Binding Transcription Factors

2012 ◽  
Vol 45 (3) ◽  
pp. 330-343 ◽  
Author(s):  
Ming Yu ◽  
Tali Mazor ◽  
Hui Huang ◽  
Hsuan-Ting Huang ◽  
Katie L. Kathrein ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 1

Role of Polycomb Repressive Complex 1 (PRC1) In Runx1 Mediated Gene Regulation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3863-3863
Author(s):  
Ming Yu ◽  
Tali Mazor ◽  
Hui Huang ◽  
Emily Huang ◽  
Katie Kathrein ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Board Of Directors ◽  
Target Genes ◽  
Polycomb Repressive Complex ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Human T Cell ◽  
Equity Ownership ◽  
Polycomb Repressive Complex 1

Abstract Abstract 3863 The transcription factor Runx1 is required for the generation of all definitive hematopoietic stem cells (HSCs), and for normal megakaryocyte, lymphocyte and granulocyte terminal maturation. Runx1 and its cofactor CBF-β are also the most common targets of chromosomal translocations in human leukemias. Somatic and germline point mutations in Runx1 occur in myelodysplastic syndrome and undifferentiated leukemias, and are associated with a poor prognosis. Despite the key roles that Runx1 plays in normal and malignant hematopoiesis, its transcriptional mechanisms remain incompletely understood. In this study, we purified Runx1 containing multiprotein complexes from megakaryocytic cells and identified several associated chromatin-remodeling complexes, including Polycomb Repressive Complex 1 (PRC1), NuRD, SWI/SNF and MLL/TrxG. Interactions were validated by independent biochemical assays and demonstrate a direct interaction between Runx1 and the PRC1 component Bmi1. ChIP-seq studies identified a large overlap between Runx1/CBF-β and Ring1b (another PRC1 core component) occupied sites, with 45% of the peaks at these genes < 200 bp from each other. ShRNA mediated gene knockdown of CBF-β shows differential gene expression of many of the co-occupied genes. Among the direct CBF-β/Ring1b co-occupied targets are other key hematopoietic transcription factors including FOG-1, SCL and Lyl1, and a number of cell adhesion related genes. ShRNA knockdown of Ring1b impairs megakaryocyte endomitosis, partially phenocopying Runx1 deficient megakaryocytes. Morpholino mediated knockdown of Ring1b or Bmi1 in zebrafish embryos reduces the number of phenotypic definitive HSCs, also partially phenocopying Runx1 morphants. We also show that Runx1/CBF-β interact with Ring1b in the human T cell line Jurkat, and that Ring1b occupies Runx1/CBF-β bound sites of key direct target genes in primary murine thymocytes, including CD4, TCRβ, and Th-POK. Surprisingly, we did not find enrichment for histone 2A monoubiquitination at most of the megakaryocytic and T-lymphocyte co-occupied sites examined, suggesting that PRC1 acts through alternate mechanisms at these genes. Collectively, these data provide evidence for a broad role of PRC1 in Runx1 mediated gene regulation. Disclosures: Zon: FATE, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Stemgent: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Cantor:Amgen, Inc: Consultancy.

scholarly journals Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mathieu F. Bakhoum ◽  
Jasmine H. Francis ◽  
Albert Agustinus ◽  
Ethan M. Earlie ◽  
Melody Di Bona ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Uveal Melanoma ◽  
Chromosomal Instability ◽  
Target Genes ◽  
Transcriptional Response ◽  
Polycomb Repressive Complex ◽  
Double Stranded Dna ◽  
Sting Pathway ◽  
Functional Analyses ◽  
Polycomb Repressive Complex 1

AbstractChromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.

scholarly journals Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes

2018 ◽  
Vol 28 (10) ◽  
pp. 1494-1507 ◽  
Author(s):  
Hamish W. King ◽  
Nadezda A. Fursova ◽  
Neil P. Blackledge ◽  
Robert J. Klose
Keyword(s):  
Target Genes ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 1

scholarly journals Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259674
Author(s):  
Stefan Nagel ◽  
Corinna Meyer
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Target Genes ◽  
Lymphoid Cells ◽  
B Cell Differentiation ◽  
Aberrant Expression ◽  
T Box ◽  
Lymphoid Malignancies

T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.

Development of a Model for the Study of PU.1 Function in Primary Human Hematopoietic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4234-4234
Author(s):  
Stephane Durual ◽  
Alexandra Rideau ◽  
Maciej Wiznerowics ◽  
Sylvie Ruault ◽  
Photis Beris ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Target Genes ◽  
Lentiviral Vector ◽  
Hematopoietic Cells ◽  
Myeloid Cell ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Erythroid Progenitors

Abstract PU.1 is one of the best-studied transcription factors governing hematopoiesis and has been shown to regulate positively differentiation of B-lymphocytes and granulocytes. PU.1 is also expressed in early erythroid progenitors and its interaction with GATA-1 was described to directly inhibit erythroid differentiation, since GATA-1 is the key regulator of erythropoiesis. In addition, the binding of GATA-1 to PU.1 was found to repress PU.1 dependent myeloid gene expression. In order to study more in detail the effect of PU.1 in primary human hematopoietic cell differentiation, we designed lentiviral vectors which allow PU.1 overexpression and PU.1 inhibition. For PU.1 overexpression, we cloned the PU.1 cDNA into the pWPIR-ires-GFP bicistronic plasmid and verified by transient transfection in 293T cells the production of PU.1 mRNA and of right sized protein. We analyzed PU.1 function by co-transfection assays into 293T cells using the pWPIR-PU.1 vector and CAT reporter genes governed by PU.1 responsive elements. By CAT ELISA assay we observed a dramatic increase in OD. The production of PU.1 mRNA and protein in Hela cells was verified by stable transduction with complete lentivectors. For PU.1 inhibition, we constructed a lentiviral vector encoding a siRNA specific for PU.1. After transduction of the K562 erythroleukemic cell line, both PU.1 mRNA and protein became undetectable, as verified by RT-PCR and Western blot, respectively, whereas GATA-1 mRNA and protein expression remained unchanged. We tested both viral constructs in an in vitro culture system, in which CD34+ hematopoietic precursors obtained from bone marrow aspirates, differentiate into mature red cells under the influence of SCF, IL-3 and Epo or into mature granulocytes by stimulation with thrombopoietin, SCF and Flt-3L. Results for cultures with PU.1 transduced cells showed inhibition of erythroid cell differentiation by 40% ± 10% (mean of three experiments) and increased myeloid proliferation, whereas cultures with siPU.1 transduced cells showed no influence on erythroid cells and strong decrease of myeloid cell proliferation (50 – 60x) and differentiation (90 % decrease of CD13+ cells). In conclusion, our model gives us the opportunity to test the function of PU.1 overexpression and/or inhibition in primary hematopoietic cells, to test the effect on target genes in various stages of differentiating precursors and the interaction with other transcription factors like GATA-1, and to analyze pathologic conditions like some forms of acute myeloid leukemia, where PU.1 was described to be mutated or downregulated.

scholarly journals Polycomb repressive complex 1 defines the nucleosome landscape but not accessibility at target genes

2018 ◽  
Author(s):  
Hamish W King ◽  
Robert J Klose
Keyword(s):  
Target Genes ◽  
Nucleosome Occupancy ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Polycomb Group ◽  
Gene Promoters ◽  
Polycomb Repressive Complex ◽  
Chromatin Domains ◽  
Genetic Ablation ◽  
Polycomb Repressive Complex 1

ABSTRACTPolycomb group (PcG) proteins are transcriptional repressors that play important roles regulating gene expression during animal development. In vitro experiments have shown that PcG protein complexes can compact chromatin limiting the activity of chromatin remodelling enzymes and access of the transcriptional machinery to DNA. In fitting with these ideas, gene promoters associated with PcG proteins have been reported to be less accessible than other gene promotors. However, it remains largely untested in vivo whether PcG proteins define chromatin accessibility or other chromatin features. To address this important question, we measured chromatin accessibility and examined the nucleosome landscape at PcG protein-bound promoters in mouse embryonic stem cells using the assay for transposase accessible chromatin (ATAC)-seq. Combined with genetic ablation strategies, we unexpectedly discover that although PcG protein-occupied gene promoters exhibit reduced accessibility, this does not rely on PcG proteins. Instead, the Polycomb repressive complex 1 (PRC1) appears to play a unique role in driving elevated nucleosome occupancy and decreased nucleosomal spacing in Polycomb chromatin domains. Our new genome-scale observations argue, in contrast to the prevailing view, that PcG proteins and Polycomb chromatin domains do not significantly affect chromatin accessibility and highlight an underappreciated complexity in the relationship between chromatin accessibility, the nucleosome landscape and PcG-mediated transcriptional repression.

scholarly journals Polycomb Repressive Complex 2-controlled Essrg regulates intestinal Microfold cell differentiation

2020 ◽  
Author(s):  
Joel Johnson George ◽  
Mikko Oittinen ◽  
Laura Martin-Diaz ◽  
Veronika Zapilko ◽  
Sharif Iqbal ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
Cell Development ◽  
Polycomb Repressive Complex ◽  
M Cell ◽  
Polycomb Repressive Complex 2 ◽  
Epigenetic Regulator ◽  
Microfold Cells ◽  
Estrogen Related Receptor

AbstractMicrofold cells (M cells) are immunosurveillance epithelial cells located in the Peyer’s patches in the intestine responsible for monitoring and transcytosis of antigens, microorganisms and pathogens. Many transcription factors, e.g., Spi-B and Sox8, necessary to M cell differentiation have been described but the exhaustive set of factors sufficient for differentiation and development of a mature M cell remains elusive. Moreover, the role of polycomb repressive complex 2 (PRC2) as an epigenetic regulator of M cell development has not yet been interrogated. Here, we show that PRC2 regulates a significant set of genes during the M cell differentiation including many transcription factors. Estrogen related receptor gamma (Esrrg) is a novel M cell specific transcription factor acting on a RankL-Rank induced NF-kB pathway, upstream of Sox8 and necessary but not sufficient for a mature M cell marker Gp2 expression. To conclude, with the aid of PRC2 target survey we identified the list of developmental genes specifically implicated in M cell development and Essrg as a necessary factor for Sox8-mediated M cell differentiation.

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