scholarly journals PRC2-Associated Chromatin Contacts in the Developing Limb Reveal a Possible Mechanism for the Atypical Role of PRC2 in HoxA Gene Expression

2019 ◽  
Vol 50 (2) ◽  
pp. 184-196.e4 ◽  
Author(s):  
Claudia Gentile ◽  
Soizik Berlivet ◽  
Alexandre Mayran ◽  
Denis Paquette ◽  
Fanny Guerard-Millet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

Long noncoding RNA HOTTIP cooperates with CCCTC-binding factor to coordinate HOXA gene expression

2018 ◽  
Vol 500 (4) ◽  
pp. 852-859 ◽  
Author(s):  
Feng Wang ◽  
Zhongqiong Tang ◽  
Honglian Shao ◽  
Jun Guo ◽  
Tao Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Binding Factor ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

scholarly journals The Arginine Methyltransferase PRMT6 Cooperates with Polycomb Proteins in Regulating HOXA Gene Expression

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0148892 ◽  
Author(s):  
Claudia Stein ◽  
René Reiner Nötzold ◽  
Stefanie Riedl ◽  
Caroline Bouchard ◽  
Uta-Maria Bauer
Keyword(s):  
Gene Expression ◽  
Arginine Methyltransferase ◽  
Polycomb Proteins ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

HOX gene expression in phenotypic and genotypic subgroups and low HOXA gene expression as an adverse prognostic factor in pediatric ALL

2010 ◽  
Vol 55 (6) ◽  
pp. 1072-1082 ◽  
Author(s):  
Julia Starkova ◽  
Blanka Zamostna ◽  
Ester Mejstrikova ◽  
Roman Krejci ◽  
Harry A. Drabkin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Factor ◽  
Hox Gene ◽  
Adverse Prognostic Factor ◽  
Pediatric All ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

scholarly journals Nup93 and CTCF co-modulate spatiotemporal dynamics and function of the HOXA gene cluster during differentiation

2019 ◽  
Author(s):  
Ajay S. Labade ◽  
Adwait Salvi ◽  
Krishanpal Karmodiya ◽  
Kundan Sengupta
Keyword(s):  
Gene Expression ◽  
Gene Locus ◽  
Nuclear Periphery ◽  
Spatiotemporal Dynamics ◽  
Differentiated Cells ◽  
Undifferentiated Cells ◽  
Dynamics And Function ◽  
Hoxa Gene Expression ◽  
And Function ◽  
Hoxa Gene

ABSTRACTNucleoporins regulate nuclear transport. In addition, nucleoporins also modulate chromatin organization and gene expression. Here we investigated the role of nucleoporin Nup93, in regulating HOXA gene expression during differentiation. ChIP-Seq analysis revealed that Nup93 associates with genes involved in development and differentiation. Furthermore, Nup93 occupancy significantly overlaps with CTCF. Interestingly, Nup93 and CTCF show antagonistic roles in regulating 3’ and 5’ end HOXA genes in undifferentiated cells. The HOXA gene locus untethered from the nuclear periphery upon Nup93 but not CTCF depletion, consistent with its upregulation. Remarkably, occupancy of Nup93 and CTCF on HOXA gene locus progressively declined during differentiation but was restored in differentiated cells, consistent with the rerepression and re-localization of the HOXA gene locus with the nuclear periphery upon differentiation. In summary, Nup93 is a key modulator of the spatiotemporal dynamics and function of the HOXA gene locus during differentiation.

ASXL1 Mutations Promote Myeloid Transformation Through Inhibition of PRC2-Mediated Gene Repression

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 405-405 ◽  
Author(s):  
Omar Abdel-Wahab ◽  
Mazhar Adli ◽  
Lindsay Saunders ◽  
Jie Gao ◽  
Alan H. Shih ◽  
...  
Keyword(s):  
Gene Expression ◽  
Research Funding ◽  
Hematopoietic Cells ◽  
Loss Of Function ◽  
Genome Wide ◽  
Hoxa Gene Expression ◽  
Primary Leukemia ◽  
Hoxa Gene

Abstract Abstract 405 Somatic mutations in ASXL1 have been identified in patients with myeloid malignancies and are associated with worsened overall survival in AML and MDS patients. However the mechanisms of myeloid transformation of ASXL1 mutations had not been delineated. We therefore performed extensive in vitro and in vivo studies to assess the functional implications of ASXL1 mutations in the hematopoietic compartment. Transcriptional and Western blot analysis demonstrated loss of ASXL1 protein in primary leukemia samples with endogenous ASXL1 mutations indicating that these mutations are loss-of-function disease alleles. Further, ASXL1 depletion by shRNA in normal and malignant hematopoietic cells leads to robust upregulation of a set of genes including the posterior HOXA cluster (HoxA5-HoxA13). Increased HoxA gene expression was confirmed in human hematopoietic stem progenitor cells targeted with ASXL1 siRNA and in mice with conditional deletion of Asxl1 in the hematopoietic compartment. Previous studies in Drosophila had revealed that Asxl forms the polycomb-repressive deubiquitinase (PR-DUB) complex with BAP1, which normally opposes the function of polycomb repressive complex 1 (PRC1) by removing H2AK119 ubiquitination. We verified that wild-type, but not mutant ASXL1 associates with BAP1 in co-immunoprecipitation studies. However, BAP1 depletion in hematopoietic cells did not result in significant changes in HoxA gene expression, suggesting that ASXL1 regulates gene expression in hematopoietic cells independent of its role in the PR-DUB complex. We therefore performed CHIP sequencing for known activating and repressive chromatin marks and histone mass spectrometry to elucidate the genome-wide effects of ASXL1 loss on chromatin state in hematopoietic cells. This allowed us to show that ASXL1 loss resulted in genome-wide loss of the transcriptionally repressive mark H3K27me3 in hematopoietic cells and primary patient samples with ASXL1 mutations. These data were supported by western blot analysis and histone mass spectrometry demonstrating a significant loss of H3K27 trimethylation in ASXL1-mutant cells. Moreover, ASXL1 mutations in primary leukemia samples are characterized by loss of H3K27 trimethylation at the HoxA locus. These data led us to hypothesize that ASXL1 interacts with the PRC2 complex; co-immunoprecipitation studies revealed that ASXL1 associates with members of the PRC2 complex including EZH2 and SUZ12 but not with the PRC1 repressive complex. Importantly, ASXL1 downregulation resulted in loss of EZH2 recruitment to the HOXA locus indicating a role of ASXL1 in recruiting the PRC2 complex to known leukemogenic loci. We next assessed the effects of ASXL1 loss in vivo by generating a conditional knock-out model of ASXL1 and also by employing shRNA to deplete ASXL1 in hematopoietic cells expressing the NRASG12D oncogene. Consonant with the in vitro data, we observed HOXA9 overexpression with ASXL1 loss/depletion in vivo. Preliminary analysis reveals that conditional, hematopoietic specific ASXL1-knockout (ASXL1fl/fl Vav-Cre) mice are characterized by progressive expansion of LSK and myeloid progenitor cells in mice less than 6 months of age. After 6 months of age a significant proportion of ASXL1fl/fl Vav-Cre mice developed leukocytosis, anemia, thrombocytopenia, and splenomegaly; pathologic analysis of tissues revealed a phenotype consistent with myelodysplasia with myeloproliferative features. Moreover, loss of ASXL1 in cooperation with expression of NRasG12D resulted in impaired survival, increased myeloproliferation, and progressive anemia consistent with MPN/MDS in vivo. Taken together, these results reveal that ASXL1 mutations result in a loss-of-function and suggest a specific role for ASXL1 in epigenetic regulation of gene expression by facilitating PRC2-mediated transcriptional repression of known leukemic oncogenes. Moreover, our in vivo data validate the importance of ASXL1 mutations in the pathogenesis of myeloid malignancies and provide insight into how mutations that inhibit PRC2 function contribute to myeloid transformation through epigenetic dysregulation of specific target genes. Disclosures: Carroll: Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding.

scholarly journals HOXA GENE EXPRESSION IMPLICATED IN TREATMENT RESISTANCE AND POOR PROGNOSIS IN GLIOBLASTOMA

2020 ◽  
Vol 6 (2) ◽  
pp. 105-110
Author(s):  
Naomi Seidu ◽  
Edward Poluyi ◽  
Chibuikem Ikwuegbuenyi ◽  
Eghosa Morgan
Keyword(s):  
Gene Expression ◽  
Poor Prognosis ◽  
Treatment Resistance ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

scholarly journals The CRM1 Nuclear Export Receptor Activates HOXA Gene Expression in Leukemogenesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2190-2190
Author(s):  
Catherine P Lavau ◽  
Jessica L Heath ◽  
William H Lee ◽  
Amanda E Conway ◽  
Daniel S Wechsler
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Transcriptional Activation ◽  
Nuclear Export ◽  
Leukemia Cells ◽  
Nuclear Pore ◽  
Myeloid Neoplasms ◽  
Hoxa Genes ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

Abstract HOXA genes are effectors of oncogenic transformation that are frequently upregulated in myeloid and T-cell acute leukemias. Chromosomal translocation-derived oncoproteins, including MLL fusions, NUP (NUP98 or NUP214) fusions or CALM-AF10, bind to HOXA genes and result in their overexpression. We have previously demonstrated that a CRM1-dependent Nuclear Export Signal (NES) within CALM is essential for CALM-AF10’s ability to upregulate HOXA genes and cause leukemia in mice. Interfering with the CRM1/CALM-AF10 interaction by either genetic or pharmacologic inhibition abolishes CALM-AF10’s ability to bind to and activate HOXA gene expression. Furthermore, we showed that CRM1 binds to HOXA loci, suggesting that CRM1 recruits CALM-AF10 to its target genes. To explore whether CRM1 is also involved in the upregulation of Hoxa genes associated with MLL- and NUP98-fusion genes, we measured Hoxa transcript levels in murine leukemia cells treated with the CRM1 inhibitor Leptomycin B (LMB). LMB is a small molecule that covalently binds to the NES binding domain of CRM1 and blocks its ability to interact with NES partner proteins. We found that treatment of MLL-AF10, MLL-ENL, NUP98-HOXA9 or NUP98-AF10 leukemia cells with LMB (1 nM, 2 hours) causes a 50% reduction of Hoxa7, Hoxa9, Hoxa10 and Hoxa11 levels, similar to what is observed in CALM-AF10 leukemia cells. This suggests that in addition to its ability to interact with CALM-AF10, CRM1 may also participate in the transcriptional activation of Hoxa genes caused by MLL- or NUP98-fusion proteins. To demonstrate the importance of the CRM1/CALM interaction in CALM-AF10-dependent oncogenesis, we studied the biological activity of an artificial CRM1-AF10 fusion protein. Using a murine bone marrow clonogenic progenitor replating assay, we found that while native CRM1 overexpression did not result in transformation, the CRM1-AF10 fusion significantly increased the self-renewal of clonogenic progenitors. This effect was even more pronounced when CRM1 was fused to the MLL partner ENL: transduction with a CRM1-ENL fusion gene caused the immortalization of clonogenic bone marrow progenitors. Both CRM1-AF10- and CRM1-ENL-transduced progenitors displayed overexpression of Hoxa genes. To investigate the leukemogenic potential of CRM1-AF10in vivo, we transplanted mice with retrovirally transduced bone marrow progenitors and found that CRM1-AF10 induces myeloid neoplasms with a low penetrance and long latency (after more than a year of observation, 5 of 15 mice developed myeloid neoplasms between 160 and 220 days). These primary CRM1-AF10 leukemias could be transplanted to secondary recipients and cause myeloid leukemias with a shorter latency. Experiments to determine the leukemogenic potential of CRM1-ENLin vivo are ongoing. In contrast to CRM1-AF10, CRM1-ENL-transduced progenitors displayed a marked proliferative advantage in all transplanted mice (assessed by the elevation in the percentage of GFP-expressing CRM1-ENL-transduced cells in the peripheral blood over time); mice transplanted 74 days ago will be followed to determine survival curves. In summary, our results demonstrate that CRM1 regulates the expression of Hoxa genes in mouse leukemia cells, and alteration of CRM1’s activity can drive murine leukemogenesis. This has implications for understanding the mechanisms of HOXA deregulation in human leukemias induced by various fusion oncoproteins. It is noteworthy that in addition to interacting directly with CALM-AF10 through the NES, CRM1 physiologically interacts with NUP98 and NUP214 to facilitate transport through the nuclear pore. Our data also suggest that the anti-tumor effects of CRM1 inhibitors (Selective Inhibitors of Nuclear Export, SINEs) currently undergoing clinical trials, could be mediated, at least in part, by their ability to block the transcriptional activation of tumor-promoting genes by CRM1. Disclosures No relevant conflicts of interest to declare.

scholarly journals MIR142 loss-of-function mutations derepress ASH1L to increase HOXA gene expression and promote leukemogenesis

2018 ◽  
pp. canres.3592.2017 ◽  
Author(s):  
Maria C. Trissal ◽  
Terrence N. Wong ◽  
Juo-Chin Yao ◽  
Rahul Ramaswamy ◽  
Iris Kuo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Loss Of Function ◽  
Hoxa Gene Expression ◽  
Hoxa Gene

scholarly journals Ezh2 Requires PHF1 To Efficiently Catalyze H3 Lysine 27 Trimethylation In Vivo

2008 ◽  
Vol 28 (8) ◽  
pp. 2718-2731 ◽  
Author(s):  
Kavitha Sarma ◽  
Raphael Margueron ◽  
Alexey Ivanov ◽  
Vincenzo Pirrotta ◽  
Danny Reinberg
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Polycomb Group ◽  
Gene Repression ◽  
Hoxa Gene Expression ◽  
Polycomb Repressive Complexes ◽  
Repressive H3k27me3 Mark ◽  
Hoxa Gene

ABSTRACT The mammalian Polycomblike protein PHF1 was previously shown to interact with the Polycomb group (PcG) protein Ezh2, a histone methyltransferase whose activity is pivotal in sustaining gene repression during development and in adulthood. As Ezh2 is active only when part of the Polycomb Repressive Complexes (PRC2-PRC4), we examined the functional role of its interaction with PHF1. Chromatin immunoprecipitation experiments revealed that PHF1 resides along with Ezh2 at Ezh2-regulated genes such as the HoxA loci and the non-Hox MYT1 and WNT1 genes. Knockdown of PHF1 or of Ezh2 led to up-regulated HoxA gene expression. Interestingly, depletion of PHF1 did correlate with reduced occupancy of Bmi-1, a PRC1 component. As expected, knockdown of Ezh2 led to reduced levels of its catalytic products H3K27me2/H3K27me3. However, reduced levels of PHF1 also led to decreased global levels of H3K27me3. Notably, the levels of H3K27me3 decreased while those of H3K27me2 increased at the up-regulated HoxA loci tested. Consistent with this, the addition of PHF1 specifically stimulated the ability of Ezh2 to catalyze H3K27me3 but not H3K27me1/H3K27me2 in vitro. We conclude that PHF1 modulates the activity of Ezh2 in favor of the repressive H3K27me3 mark. Thus, we propose that PHF1 is a determinant in PcG-mediated gene repression.

Sign in / Sign up

Export Citation Format

Share Document