scholarly journals Role of Polycomb Repressive Complex 2 in Regulation of Human Transcription Factor Gene Expression

2021 ◽  
Author(s):  
Jay C. Brown
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factor Gene ◽  
Polycomb Repressive Complex ◽  
Factor Gene ◽  
Polycomb Repressive Complex 2 ◽  
Human Transcription Factor

Context Dependent Role of Polycomb Repressive Complex 2 in Acute Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 610-610
Author(s):  
Etienne Danis ◽  
Taylor Yamauchi ◽  
Kristen Echanique ◽  
Jessica Haladyna ◽  
Huafeng Xie ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Acute Leukemia ◽  
Murine Models ◽  
Polycomb Repressive Complex ◽  
Cell Precursor ◽  
Polycomb Repressive Complex 2

Abstract Polycomb Repressive Complex 2 (PRC2) is a multi-protein complex with important roles in development and cancer. Both hyper- and hypoactivity of PRC2 are associated with blood-related malignancies. Activating mutations of the PRC2 methyltransferase EZH2 have been found in human B-lineage lymphomas. Inactivating mutations of PRC2 components EZH2, EED and SUZ12 have been described in early T-cell Precursor ALL (ETP-ALL) and inactivating PRC2-alterations are found in Myelodysplastic and Myeloproliferative Syndromes. The mechanisms underlying this paradox are incompletely understood. We here investigate the context dependent role of PRC2 in murine models. We initially studied PRC2 in normal hematopoiesis: Chip-seq analysis of the PRC2-mediated H3K27me3 chromatin mark demonstrates that many genes highly expressed in immature hematopoiesis gain H3K27me3 in the developmental transition from more immature Lin-Sca1+Kit+ (LSK) cells to lineage committed Granulocyte Macrophage Progenitors (GMPs). Transcription of these genes is enriched in EZH2ko GMP compared to EZH2ffGMP by Gene Set Enrichment Analysis (GSEA). These data suggest that PRC2 is important for the silencing of immature gene expression programs in the developmental transition from LSK to GMP. We next analyzed the role of PRC2 in two murine models of acute leukemia: MLL-AF9 driven leukemia, and a model of early T-cell precursor T-ALL (ETP-ALL). In MLL-AF9 leukemia, we previously found that inactivation of Eed completely abrogate leukemogenesis in vitro and in vivo. We now report that genetic inactivation of the tumor suppressor Cdkn2a (a canonical PRC2 target) partially rescued MLL-AF9 mediated leukemia in vitro and in vivo. However, Cdkn2akoEEDko MLL-AF9 leukemia remained compromised. In vitro growth was reduced to approximately 10% of Eedff controls. While control MLL-AF9 leukemia developed in vivo in 100% of the recipients, Cdkn2akoEEDkoMLL-AF9 leukemia developed with significantly prolonged latency and incomplete penetrance (25%). RNAseq analysis revealed that high level expression of genes with established roles in MLL-AF9 leukemia such as HoxA9, Cdk6 and Jmjd1c unexpectedly depends on Eed. These data are in keeping with the absence of alterations in PRC2-components in human MLL-rearranged leukemia. In contrast, PRC2 core components (EZH2/EED/SUZ12) are deleted or mutated in > 40% of ETP-ALL. ETP-ALL also often has direct or indirect activation of the RAS-pathway, and carries frequent deletions of the CDKN2A locus. To model the effects of EED and EZH2-inactivation in ETP-ALL, we established Cdkn2akoEedff vs Cdkn2akoEedko, and Cdkn2akoEzh2ff vs Cdkn2akoEZH2koleukemias by transduction with NRASQ61K followed by expansion on OP9DL1 stroma cells to activate T-lineage differentiation via Notch-signaling. Cdkn2ako NRASQ61K leukemia showed an immunophenotype similar to human ETP-ALL (positive for c-Kit, CD5 and myeloid markers and mostly negative for CD4/8). Inactivation of Eed or Ezh2 in this model led to a shortening of latency (p=0.03 for Eed, p=0.0001 for Ezh2). RNAseq revealed enrichment of genes associated with murine DN1 thymocytes and with human ETP-ALL in Eedko vs Eedff Cdkn2ako NRASQ61K leukemia. These genesets showed even more pronounced enrichment in Ezh2kocompared to Ezh2ff Cdkn2ako NRASQ61K leukemia. Genes highly expressed in early hematopoiesis were enriched in Eedko and Ezh2ko cells in both, the MLL-AF9 and NRASQ61K leukemia models. However, there was an opposing effect on HoxA9 gene expression, with PRC2 inactivation leading to decreased HoxA9 expression in MLL-AF9, and increased HoxA9 expression in Cdkn2ako NRASQ61K leukemia. Decreased HoxA9 has been shown to impair MLL-AF9 leukemia growth. To test the functional significance of elevated HoxA9-levels in the Eedko and EZH2koNRASQ61K leukemias, we co-expressed HoxA9 and NRASQ61K in the presence of intact Eed and Ezh2 loci. Preliminary data suggest that HoxA9 accelerates leukemia development in this setting. Alterations in chromatin modifiers, including PRC2, are frequent in leukemia and lymphoma. Our data demonstrate that manipulation of PRC2 can have opposite effects on leukemia phenotype and expression of key PRC2-repressed genes such as HoxA9 in the context of different tumors. We are currently characterizing the mechanisms leading to divergent outcomes of PRC2 manipulation in MLL-AF9 leukemia compared to NRASQ61K ETP-like leukemia. Disclosures Armstrong: Epizyme : Consultancy.

scholarly journals THE CHARACTERISTICS OF MIRNA BINDING SITES IN MRNA OF ZFHX3 GENE AND ITS ORTHOLOGS

2018 ◽  
Vol 22 (4) ◽  
pp. 438-444 ◽  
Author(s):  
A. М. Kondybayeva ◽  
A. N. Akimniyazova ◽  
S. U. Kamenova ◽  
A. Т. Ivashchenko
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Binding Sites ◽  
Animal Species ◽  
Biological Function ◽  
Dna Binding Proteins ◽  
Trinucleotide Repeats ◽  
Transcription Factor Gene ◽  
Factor Gene

Transcription factor gene ZFHX3 is one of the candidate genes involved in stroke development. The ZFHX3 protein contains oligopeptides encoded by trinucleotide repeats (TNRs). TNR variability is considered to be one of the causes of the disease, but their biological function has not yet been established. We assume that TNRs are the binding sites of miRNA to mRNA and are involved in regulation of ZFHX3 gene expression. The characteristics of miRNA–mRNA interaction were determined using MirTarget software. It has been shown that the first TNR in mRNA of the human ZFHX3 gene consists of the seven consecutive miR-12-32603-3p binding encoding polyGlu. The ZFHX3 protein of human polyGlu contains 30 Glu. In the orthologous proteins of 36 animal species the length of polyGlu varied from 27 Glu to 33 Glu. Negatively charged polyGlu of the ZFHX3 transcription factor probably interacted with positive DNA-binding proteins. The following mRNA region of the ZFHX3 gene contained the binding sites for miR-17-39416-3p, miR-5-15733-3p, miR-9-20317-3 encoding polyAla by 15 Ala lengths. In the 33 ZFHX3 orthologous proteins polyAla had the same length. The mRNA region of the human ZFHX3 gene with binding polysite of miR-1322-3p encoded polyGln consisting of 19 Gln. In the 41 orthologs of the ZFHX3 protein the length of polyGln varied from seven Gln to 23 Gln. The binding sites of miR-2-6184-3p, miR-5-14114-5p and miR-19-43437-5p were located with overlapping nucleotides sequences, and encode polyPro. In ZFHX3 human polyPro consisted of 12 Pro. In the orthologs, polyPro contained from 10 Pro to 14 Pro. The binding sites of miR-17-39416-3p, miR-9-20317-3p, miR-1-1819-3p, miR-5-15733-3p, miR-6-17815-3p, miR-18-39953-5p, miR-26862-5p, miR-1260b and miR-X-48174-3p in human ZFHX3 encoded polyGly by 22 Gly length. In the 28 orthologs of ZFHX3 the length of polyGly decreased to 11 Gly. The TNR regions could simultaneously bind several miRNAs, which increased the dependence of gene expression on miRNA. The oligopeptides encoded by the binding polysites of miRNA in mRNA in the orthologous ZFHX3 proteins were flanked by conserved oligopeptides.

scholarly journals Role of polycomb repressive complex 2 in regulation of human transcription factor gene expression

2021 ◽  
Author(s):  
Jay Brown
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dna Sequences ◽  
Binding Sites ◽  
Regulatory Control ◽  
Polycomb Repressive Complex ◽  
Control Of Gene Expression ◽  
Polycomb Repressive Complex 2

Control of gene expression is now recognized as a central issue in the field of molecular biology. We now know the sequences of many genomes including that of the human genome, and we know the nature of many pathways involved in control of gene expression. It remains difficult, however, to look at the DNA sequences surrounding a particular gene and tell which methods of regulatory control are in use. I have been pursuing the idea that progress might be made by comparing the regulatory regions of paired gene populations in which one population is strongly expressed and the other weakly. Here I report the results obtained with human genes encoding transcription factors (TF). In this population, broadly expressed genes are strongly expressed while tissue targeted TF expression is suppressed in most tissues. The results demonstrated that the promoter region of broadly expressed TF genes is enriched in binding sites for POLR2A, a component of RNA polymerase II while promoters of tissue targeted genes are enriched in EZH2, a subunit of polycomb repressive complex 2 (PRC2). It was rare to observe promoters with binding sites for both POLR2A and EZH2. The findings are interpreted to indicate that strong expression of broadly expressed TF genes is due to the presence of RNA polymerase II at the promoter while weak expression of tissue targeted promoters results from the presence of PRC2. Finally, transcription factor families were compared in the proportion of broadly expressed and tissue targeted genes they contain. The results demonstrated that most families possess both broadly expressed and tissue targeted members. For instance, this was the case with 16 of 20 TF families examined. The results are interpreted to indicate that while individual TFs such as EZH2 may be specific for broadly expressed or tissue targeted genes, this is not a property of most TF families.

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