scholarly journals The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

2020 ◽  
Author(s):  
Kami Ahmad ◽  
Steven Henikoff
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Gene Silencing ◽  
Master Regulator ◽  
Histone H3k27 ◽  
Chromatin Profiling ◽  
Polycomb Repressive Complex 1 ◽  
Development Proceeds ◽  
Simple Combination

AbstractDevelopment proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In some cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that expression of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 domains are globally reduced with oncohistone expression, suggesting that previous developmental programs must be silenced for effective transformation. Strikingly, mis-expressed Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb Repressive Complex 1 components. Our results imply that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.

scholarly journals The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009225
Author(s):  
Kami Ahmad ◽  
Steven Henikoff
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Transcriptome Profiling ◽  
Master Regulator ◽  
Developmental Program ◽  
Histone H3k27 ◽  
Chromatin Profiling ◽  
Development Proceeds ◽  
Simple Combination

Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In certain cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that production of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 of domains is generally reduced upon oncohistone production, suggesting that a previous developmental program must be silenced for effective transformation. Strikingly, Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb silencing components. Transcriptome profiling of elongating RNA Polymerase II implicates the mis-regulation of signaling factors in overgrowth. Our results demonstrate that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.

scholarly journals HbxB Is a Key Regulator for Stress Response and β-Glucan Biogenesis in Aspergillus nidulans

2021 ◽  
Vol 9 (1) ◽  
pp. 144
Author(s):  
Sung-Hun Son ◽  
Mi-Kyung Lee ◽  
Ye-Eun Son ◽  
Hee-Soo Park
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Aspergillus Nidulans ◽  
Deletion Mutant ◽  
Phenotypic Analysis ◽  
Spore Viability ◽  
Fungal Development ◽  
Expression Of Genes ◽  
Trehalose Biosynthesis

Homeobox transcription factors are conserved in eukaryotes and act as multi-functional transcription factors in filamentous fungi. Previously, it was demonstrated that HbxB governs fungal development and spore viability in Aspergillus nidulans. Here, the role of HbxB in A. nidulans was further characterized. RNA-sequencing revealed that HbxB affects the transcriptomic levels of genes associated with trehalose biosynthesis and response to thermal, oxidative, and radiation stresses in asexual spores called conidia. A phenotypic analysis found that hbxB deletion mutant conidia were more sensitive to ultraviolet stress. The loss of hbxB increased the mRNA expression of genes associated with β-glucan degradation and decreased the amount of β-glucan in conidia. In addition, hbxB deletion affected the expression of the sterigmatocystin gene cluster and the amount of sterigmatocystin. Overall, these results indicated that HbxB is a key transcription factor regulating trehalose biosynthesis, stress tolerance, β-glucan degradation, and sterigmatocystin production in A.nidulans conidia.

scholarly journals BRN2 is a non-canonical melanoma tumor-suppressor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Hamm ◽  
Pierre Sohier ◽  
Valérie Petit ◽  
Jérémy H. Raymond ◽  
Véronique Delmas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
The Other ◽  
Pi3k Signaling ◽  
Melanoma Tumor ◽  
Temporal Regulation ◽  
Metastatic Colonization ◽  
Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

scholarly journals How cancer cells remodel lipid metabolism: strategies targeting transcription factors

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Do-Won Jeong ◽  
Seulbee Lee ◽  
Yang-Sook Chun
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Lipid Metabolism ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Factors Associated ◽  
Modeling Techniques ◽  
Related Enzyme ◽  
Potential Strategy

AbstractReprogramming of lipid metabolism has received increasing recognition as a hallmark of cancer cells because lipid dysregulation and the alteration of related enzyme profiles are closely correlated with oncogenic signals and malignant phenotypes, such as metastasis and therapeutic resistance. In this review, we describe recent findings that support the importance of lipids, as well as the transcription factors involved in cancer lipid metabolism. With recent advances in transcription factor analysis, including computer-modeling techniques, transcription factors are emerging as central players in cancer biology. Considering the limited number and the crucial role of transcription factors associated with lipid rewiring in cancers, transcription factor targeting is a promising potential strategy for cancer therapy.

scholarly journals Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators

2020 ◽  
Vol 21 (19) ◽  
pp. 7388
Author(s):  
Federica Zinghirino ◽  
Xena Giada Pappalardo ◽  
Angela Messina ◽  
Francesca Guarino ◽  
Vito De Pinto
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Promoter Activity ◽  
Expression Profiles ◽  
Transcriptional Regulators ◽  
General Role ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 1

VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs’ presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon–intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.

scholarly journals AP1 Transcription Factors in Epidermal Differentiation and Skin Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Richard L. Eckert ◽  
Gautam Adhikary ◽  
Christina A. Young ◽  
Ralph Jans ◽  
James F. Crish ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Dominant Negative ◽  
Epidermal Differentiation ◽  
Cancer Development ◽  
Multiple Cells ◽  
Different Levels ◽  
Factor Function

AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Variousin vivogenetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development.

scholarly journals Role Of WOX And KNOX Transcription Factors In Plant Development And Tumor Formation

2006 ◽  
Vol 4 (4) ◽  
pp. 3-9
Author(s):  
Maria A Osipova ◽  
Elena A Dolgikh ◽  
Ludmila A Lutova
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Plant Development ◽  
Plant Hormones ◽  
Tumor Formation ◽  
Animal Tumor ◽  
The Common ◽  
Meristem Maintenance

Homeodomain-containing transcription factors are the important regulators of multicellular organism's development. Plant transcription factors WOX and KNOX play the key role in meristem maintenance, controlling cell proliferation and preventing differentiation. The precise mechanism of WOX and KNOX action hasn't been well studied, however these transcription factors were shown to play the important role in plant hormones homeostasis, cytokinins in particular. Plant transcription factors of KNOX group demonstrate the similarities in structure and are supposed have the common origin with animal transcription factors of MEIS group. This review describes WOX and KNOX transcription factor families, their interaction with plant hormones. The role of homeodomain-containing transcription factors in plant and animal tumor formation is discussed.

scholarly journals 2-hydroxyglutarate inhibits MyoD-mediated differentiation by preventing H3K9 demethylation

2019 ◽  
Vol 116 (26) ◽  
pp. 12851-12856 ◽  
Author(s):  
Juan-Manuel Schvartzman ◽  
Vincent P. Reuter ◽  
Richard P. Koche ◽  
Craig B. Thompson
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Competitive Inhibition ◽  
Mesenchymal Cells ◽  
Genome Wide ◽  
Idh Mutations ◽  
Differentiation Block

Oncogenic IDH1/2 mutations produce 2-hydroxyglutarate (2HG), resulting in competitive inhibition of DNA and protein demethylation. IDH-mutant cancer cells show an inability to differentiate but whether 2HG accumulation is sufficient to perturb differentiation directed by lineage-specifying transcription factors is unknown. A MyoD-driven model was used to study the role of IDH mutations in the differentiation of mesenchymal cells. The presence of 2HG produced by oncogenic IDH2 blocks the ability of MyoD to drive differentiation into myotubes. DNA 5mC hypermethylation is dispensable while H3K9 hypermethylation is required for this differentiation block. IDH2-R172K mutation results in H3K9 hypermethylation and impaired accessibility at myogenic chromatin regions but does not result in genome-wide decrease in accessibility. The results demonstrate the ability of the oncometabolite 2HG to block transcription factor-mediated differentiation in a molecularly defined system.

scholarly journals Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis

2020 ◽  
Vol 21 (22) ◽  
pp. 8460
Author(s):  
Min Young Kim ◽  
Bowen Yan ◽  
Suming Huang ◽  
Yi Qiu
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Gene Activation ◽  
Bhlh Transcription Factor ◽  
Nucleosome Remodeling ◽  
Hdac Activity ◽  
Histone Deacetylase 1

Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has been shown that HDAC1 interacts with and modulates all essential transcription factors for erythropoiesis. During erythropoiesis, histone deacetylase activity is dramatically reduced. Consistently, inhibition of HDAC activity promotes erythroid differentiation. The reduction of HDAC activity not only results in the activation of transcription activators such as GATA-1 (GATA-binding factor 1), TAL1 (TAL BHLH Transcription Factor 1) and KLF1 (Krüpple-like factor 1), but also represses transcription repressors such as PU.1 (Putative oncogene Spi-1). The reduction of histone deacetylase activity is mainly through HDAC1 acetylation that attenuates HDAC1 activity and trans-repress HDAC2 activity through dimerization with HDAC1. Therefore, the acetylation of HDAC1 can convert the corepressor complex to an activator complex for gene activation. HDAC1 also can deacetylate non-histone proteins that play a role on erythropoiesis, therefore adds another layer of gene regulation through HDAC1. Clinically, it has been shown HDACi can reactivate fetal globin in adult erythroid cells. This review will cover the up to date research on the role of HDAC1 in modulating key transcription factors for erythropoiesis and its clinical relevance.

scholarly journals Cancer and pulmonary hypertension: Learning lessons and real-life interplay

2020 ◽  
Vol 2020 (1) ◽  
Author(s):  
Soni Savai Pullamsetti ◽  
Sreenath Nayakanti ◽  
Prakash Chelladurai ◽  
Argen Mamazhakypov ◽  
Siavash Mansouri ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Real Life ◽  
Hallmarks Of Cancer ◽  
Driving Mechanisms

This article reviews the scientific reasons that support the intriguing vision of pulmonary hypertension (PH) as a disease with a cancer-like nature and to understand whether this pointof view may have fruitful consequences for the overall management of PH. This review compares cancer and PH in view of Hanahan and Weinberg’s principles (i.e., hallmarks of cancer) with an emphasis on hyperproliferative, metabolic, and immune/inflammatory aspects of the disease.In addition, this review provides a perspective on the role of transcription factors and chromatin and epigenetic aberrations, besides genetics, as ‘‘common driving mechanisms’’ of PH hallmarks and the foreseeable use of transcription factor/epigenome targeting as multitarget approach against the hallmarks of PH. Thus, recognition of the widespread applicability and analogy of these concepts will increasingly affect the development of new means of PH treatment.

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