6 results on '"Avinash Govind Bahirvani"'
Search Results
2. Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells
- Author
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Cherry Ee Lin Ng, Daniel G. Tenen, Cai Ping Koh, Takashi Sonoki, Vinay Tergaonkar, Yi Zhang, Archibald S. Perkins, Avinash Govind Bahirvani, Zakir Hossain, Linsen Du, Byrappa Venkatesh, Tomomasa Yokomizo, Chelsia Qiuxia Wang, Akiko Niibori-Nambu, Motomi Osato, Yoshiaki Ito, Hiroki Hosoi, Dominic Chih-Cheng Voon, and Michelle Meng Huang Mok
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Transgene ,Hematopoietic stem cell ,Biology ,Phenotype ,Cell biology ,Transplantation ,Haematopoiesis ,chemistry.chemical_compound ,medicine.anatomical_structure ,RUNX1 ,chemistry ,medicine ,Stem cell ,Enhancer - Abstract
SummaryA cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs which are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.
- Published
- 2021
3. Activation of EVI1 transcription by the LEF1/β-catenin complex with p53-alteration in myeloid blast crisis of chronic myeloid leukemia
- Author
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Motomi Osato, Nawin Manachai, Avinash Govind Bahirvani, Yusuke Saito, Kazuhiro Morishita, and Shingo Nakahata
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Transcriptional Activation ,0301 basic medicine ,Myeloid ,Lymphoid Enhancer-Binding Factor 1 ,Biophysics ,Biology ,Biochemistry ,Fusion gene ,Mice ,03 medical and health sciences ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Proto-Oncogenes ,Transcriptional regulation ,medicine ,Animals ,Humans ,neoplasms ,Molecular Biology ,beta Catenin ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Imatinib ,Cell Biology ,medicine.disease ,MDS1 and EVI1 Complex Locus Protein ,DNA-Binding Proteins ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Phosphorylation ,Catenin complex ,Tumor Suppressor Protein p53 ,Blast Crisis ,Transcription Factors ,medicine.drug - Abstract
The presence of a BCR-ABL1 fusion gene is necessary for the pathogenesis of chronic myeloid leukemia (CML) through t(9;22)(q34;q11) translocation. Imatinib, an ABL tyrosine kinase inhibitor, is dramatically effective in CML patients; however, 30% of CML patients will need further treatment due to progression of CML to blast crisis (BC). Aberrant high expression of ecotropic viral integration site 1 (EVI1) is frequently observed in CML during myeloid-BC as a potent driver with a CML stem cell signature; however, the precise molecular mechanism of EVI1 transcriptional regulation during CML progression is poorly defined. Here, we demonstrate the transcriptional activity of EVI1 is dependent on activation of lymphoid enhancer-binding factor 1 (LEF1)/β-catenin complex by BCR-ABL with loss of p53 function during CML-BC. The activation of β-catenin is partly dependent on BCR-ABL expression through enhanced GSK3β phosphorylation, and EVI1 expression is directly enhanced by the LEF1/β-catenin complex bound to the EVI1 promoter region. Moreover, the loss of p53 expression is inversely correlated with high expression of EVI1 in CML leukemia cells with an aggressive phase of CML, and a portion of the activation mechanism of EVI1 expression is dependent on β-catenin activation through GSK3β phosphorylation by loss of p53. Therefore, we found that the EVI1 activation in CML-BC is dependent on LEF1/β-catenin activation by BCR-ABL expression with loss of p53 function, representing a novel selective therapeutic approach targeting myeloid blast crisis progression.
- Published
- 2017
4. Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines
- Author
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Takashi Sonoki, Giselle Sek Suan Nah, Avinash Govind Bahirvani, Alan Prem Kumar, Yoshiaki Ito, Daniel G. Tenen, Hiroki Hosoi, Michelle Meng Huang Mok, Akiko Niibori-Nambu, Takaomi Sanda, and Motomi Osato
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0301 basic medicine ,Herpesvirus 4, Human ,Genes, myc ,Biology ,medicine.disease_cause ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Super-enhancer ,Protein Domains ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Enhancer ,Gene ,Transcription factor ,B cell ,Cell Proliferation ,B-Lymphocytes ,Cell growth ,G1 Phase ,Proteins ,Azepines ,General Medicine ,Triazoles ,Burkitt Lymphoma ,Epstein–Barr virus ,digestive system diseases ,Bromodomain ,Cell biology ,Core Binding Factor Alpha 3 Subunit ,Enhancer Elements, Genetic ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,CRISPR-Cas Systems - Abstract
Epstein-Barr virus nuclear antigens 2 (EBNA2) mediated super-enhancers, defined by in silico data, localize near genes associated with B cell transcription factors including RUNX3. However, the biological function of super-enhancer for RUNX3 gene (seR3) remains unclear. Here, we show that two seR3s, tandemly-located at 59- and 70-kb upstream of RUNX3 transcription start site, named seR3 –59h and seR3 –70h, are required for RUNX3 expression and cell proliferation in Epstein-Barr virus (EBV)-positive malignant B cells. A BET bromodomain inhibitor, JQ1, potently suppressed EBV-positive B cell growth through the reduction of RUNX3 and MYC expression. Excision of either or both seR3s by employing CRISPR/Cas9 system resulted in the decrease in RUNX3 expression and the subsequent suppression of cell proliferation and colony forming capability. The expression of MYC was also reduced when seR3s were deleted, probably due to the loss of trans effect of seR3s on the super-enhancers for MYC. These findings suggest that seR3s play a pivotal role in expression and biological function of both RUNX3 and MYC. seR3s would serve as a potential therapeutic target in EBV-related widespread tumors.
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- 2021
5. G9a, a multipotent regulator of gene expression
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Reshma Taneja, Vinay Kumar Rao, Shilpa Rani Shankar, Narendra Bharathy, Avinash Govind Bahirvani, and Jin Rong Ow
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Regulation of gene expression ,Cancer Research ,biology ,Activator (genetics) ,Cellular differentiation ,Review ,Histone-Lysine N-Methyltransferase ,Cell biology ,Repressor Proteins ,EHMT2 ,Histone ,Gene Expression Regulation ,Neoplasms ,Gene expression ,Trans-Activators ,Cancer research ,biology.protein ,Animals ,Humans ,Molecular Biology ,Cell aging ,Cellular Senescence - Abstract
Lysine methylation of histone and non-histone substrates by the methyltransferase G9a is mostly associated with transcriptional repression. Recent studies, however, have highlighted its role as an activator of gene expression through mechanisms that are independent of its methyltransferase activity. Here we review the growing repertoire of molecular mechanisms and substrates through which G9a regulates gene expression. We also discuss emerging evidence for its wide-ranging functions in development, pluripotency, cellular differentiation and cell cycle regulation that underscore the complexity of its functions. The deregulated expression of G9a in cancers and other human pathologies suggests that it may be a viable therapeutic target in various diseases.
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- 2013
6. Stra13 and Sharp-1, the Non-Grouchy Regulators of Development and Disease
- Author
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Yong Hua Tan, Avinash Govind Bahirvani, Jin Rong Ow, Reshma Taneja, and Yu Jin
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Genetics ,Histone ,Cellular differentiation ,Histone methyltransferase ,SUMO protein ,biology.protein ,Biology ,Corepressor ,HDAC1 ,Tissue homeostasis ,Chromatin ,Cell biology - Abstract
Stra13 and Sharp-1 are transcriptional repressors that share domain structure similarity with members of the basic helix-loop-helix-Orange subfamily. In contrast to other members that include Hes and Hey proteins, transcriptional repression mediated by Stra13 and Sharp-1 does not involve recruitment of the corepressor Groucho. Both proteins undergo sumoylation at evolutionarily conserved sites, and this posttranslational modification serves as a platform for association with chromatin-modifying enzymes including histone deacetylases and histone methyltransferases. In addition to being widely expressed during embryonic development and in adult tissues, the expression of both genes is induced by a number of stimuli. Loss-of-function and gain-of-function studies have demonstrated their function in cellular differentiation and regeneration, in regulation of circadian rhythms, immune homeostasis, and metabolism. Given their diverse physiological functions in several tissues, it is not surprising that deregulated expression of Stra13 and Sharp-1 is apparent in human pathologies. Here, we review our current understanding of their cellular functions that suggest a requirement in maintenance of tissue homeostasis.
- Published
- 2014
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