scholarly journals Altering Mammalian Transcription Networking with Adaadi: An Inhibitor of Atp-Dependent Chromatin Remodeling

2019 ◽  
Author(s):  
Radhakrishnan Rakesh ◽  
Saddam Hussain ◽  
Kaveri Goel ◽  
Soni Sharma ◽  
Deepa Bisht ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Cancer Progression ◽  
Mammalian Cells ◽  
Transcriptional Control ◽  
Cellular Proliferation ◽  
Rna Seq ◽  
Epigenetic Factors ◽  
Aminoglycoside Phosphotransferases ◽  
Migration Of Cells

ABSTRACTTranscriptional control has been earnestly pursued for the regulation of cellular proliferation associated with cancer progression. The foundational paradigm of targeting transcription factors has yielded exquisite specificity, but many factors cannot yet be targeted. In contrast, targeting epigenetic factors to control chromatin structure and consequential gene expression generally yields more global effects on transcription. Our working paradigm targets neither specific transcription factors nor global epigenetic factors but ATP-dependent chromatin remodeling factors that regulate expression of a limited set of genes. Active DNA-dependent ATPase A Domain inhibitor (ADAADi) synthesized by aminoglycoside phosphotransferases is the first-in-class inhibitor of ATP-dependent chromatin remodeling proteins that targets the ATPase domain of these proteins. Mammalian cells are sensitive to ADAADi but cell lines are variable in their individual responses to the inhibitor. The ADAADi product can be generated from a variety of aminoglycoside substrates with cells showing differential responses to ADAADi depending on the starting aminoglycoside. RNA seq analysis demonstrated that targeting the chromatin remodeling by treatment with a sub-lethal concentration of ADAADi yields alterations to the transcriptional network of the cell. Predominantly, the tumor-promoting genes were repressed while pro-apoptotic and tumor suppressors genes were upregulated on treatment with ADAADi, leading to apoptotic-type cell death. Treatment with ADAADi reversed the EMT process as well as inhibited migration of cells and their colony forming ability. In conjunction with the previous report that treatment with ADAADi regresses tumors in mouse model, this chromatin remodeling inhibitor shows promising anti-tumor properties by targeting the main hallmarks of cancer.

scholarly journals Altering mammalian transcription networking with ADAADi: An inhibitor of ATP-dependent chromatin remodeling

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251354
Author(s):  
Radhakrishnan Rakesh ◽  
Upasana Bedi Chanana ◽  
Saddam Hussain ◽  
Soni Sharma ◽  
Kaveri Goel ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Mammalian Cells ◽  
Structural Integrity ◽  
Helicase Domain ◽  
Cellular Functions ◽  
Damage Response ◽  
A Cell ◽  
Du145 Cells ◽  
Apoptotic Genes ◽  
Migration Of Cells

Active DNA-dependent ATPase A Domain inhibitor (ADAADi) is the only known inhibitor of ATP-dependent chromatin remodeling proteins that targets the ATPase domain of these proteins. The molecule is synthesized by aminoglycoside phosphotransferase enzyme in the presence of aminoglycosides. ADAADi interacts with ATP-dependent chromatin remodeling proteins through motif Ia present in the conserved helicase domain, and thus, can potentially inhibit all members of this family of proteins. We show that mammalian cells are sensitive to ADAADi but with variable responses in different cell lines. ADAADi can be generated from a wide variety of aminoglycosides; however, cells showed differential response to ADAADi generated from various aminoglycosides. Using HeLa and DU145 cells as model system we have explored the effect of ADAADi on cellular functions. We show that the transcriptional network of a cell type is altered when treated with sub-lethal concentration of ADAADi. Although ADAADi has no known effects on DNA chemical and structural integrity, expression of DNA-damage response genes was altered. The transcripts encoding for the pro-apoptotic proteins were found to be upregulated while the anti-apoptotic genes were found to be downregulated. This was accompanied by increased apoptosis leading us to hypothesize that the ADAADi treatment promotes apoptotic-type of cell death by upregulating the transcription of pro-apoptotic genes. ADAADi also inhibited migration of cells as well as their colony forming ability leading us to conclude that the compound has effective anti-tumor properties.

scholarly journals Systematic reconstruction of the cellular trajectories of mammalian embryogenesis

2021 ◽  
Author(s):  
Chengxiang Qiu ◽  
Junyue Cao ◽  
Tony Li ◽  
Sanjay Srivatsan ◽  
Xingfan Huang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Single Cell ◽  
Cellular Proliferation ◽  
Spatial Distributions ◽  
Rna Seq ◽  
Cell Type ◽  
Mammalian Development ◽  
Mammalian Embryogenesis ◽  
Automated Procedures

Mammalian embryogenesis is characterized by rapid cellular proliferation and diversification. Within a few weeks, a single cell zygote gives rise to millions of cells expressing a panoply of molecular programs, including much of the diversity that will subsequently be present in adult tissues. Although intensively studied, a comprehensive delineation of the major cellular trajectories that comprise mammalian development in vivo remains elusive. Here we set out to integrate several single cell RNA-seq datasets (scRNA-seq) that collectively span mouse gastrulation and organogenesis. We define cell states at each of 19 successive stages spanning E3.5 to E13.5, heuristically connect them with their pseudo-ancestors and pseudo-descendants, and for a subset of stages, deconvolve their approximate spatial distributions. Despite being constructed through automated procedures, the resulting trajectories of mammalian embryogenesis (TOME) are largely consistent with our contemporary understanding of mammalian development. We leverage TOME to nominate transcription factors (TF) and TF motifs as key regulators of each branch point at which a new cell type emerges. Finally, to facilitate comparisons across vertebrates, we apply the same procedures to single cell datasets of zebrafish and frog embryogenesis, and nominate "cell type homologs" based on shared regulators and transcriptional states.

scholarly journals LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Luca Ducoli ◽  
Saumya Agrawal ◽  
Eliane Sibler ◽  
Tsukasa Kouno ◽  
Carlotta Tacconi ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Target Genes ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Rna Seq ◽  
Epigenetic Factors ◽  
Ample Evidence ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

AbstractRecent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determine a comprehensive map of lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs), combining RNA-Seq and CAGE-Seq. Subsequent antisense oligonucleotide-knockdown transcriptomic profiling of two LEC- and two BEC-specific lncRNAs identifies LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein interaction studies, and phenotype rescue analyses reveal that LETR1 is a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides several lines of evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.

scholarly journals Towards understanding the regulation of histone H1 somatic subtypes with OMICs

2020 ◽  
Author(s):  
Inma Ponte ◽  
Marta Andrés ◽  
Albert Jordan ◽  
Alicia Roque
Keyword(s):  
Transcription Factors ◽  
Transcriptional Control ◽  
Histone H1 ◽  
Variable Number ◽  
Model Systems ◽  
Order Structure ◽  
Rna Seq ◽  
Public Repositories ◽  
Using Data ◽  
First Time

AbstractBackgroundHistone H1 is involved in the regulation of chromatin higher-order structure and compaction. In humans, histone H1 is a multigene family with seven subtypes differentially expressed in somatic cells. Which are the regulatory mechanisms that determine the variability of the H1 complement is a long-standing biological question regarding histone H1. We have used a new approach based on the integration of OMICs data to address this question.ResultsWe have examined the 3D-chromatin structure, the binding of transcription factors (TFs), and the expression of somatic H1 genes in human cell lines, using data from public repositories, such as ENCODE. Analysis of Hi-C, ChIP-seq, and RNA-seq data, have shown that transcriptional control has a greater impact on H1 regulation than previously thought. Somatic H1 genes located in TADs show higher expression than in boundaries. H1 genes are targeted by a variable number of transcription factors including cell cycle-related TFs, and tissue-specific TFs, suggesting a finetuned, subtype-specific transcriptional control. We describe, for the first time, that all H1 somatic subtypes are under transcriptional co-regulation. The replication-independent subtypes, which are encoded in different chromosomes, isolated from other histone genes are also co-regulated with the rest of the somatic H1 genes, indicating that transcriptional co-regulation extends beyond the histone cluster.ConclusionsTranscriptional control and transcriptional co-regulation explain, at least in part, the variability of H1 complement, the fluctuations of H1 subtypes during development, and also the compensatory effects observed, in model systems, after perturbation of one or more H1 subtypes.

scholarly journals The “Janus” Role of C/EBPs Family Members in Cancer Progression

2020 ◽  
Vol 21 (12) ◽  
pp. 4308 ◽  
Author(s):  
Manlio Tolomeo ◽  
Stefania Grimaudo
Keyword(s):  
Transcription Factors ◽  
Cancer Progression ◽  
Tumor Suppressors ◽  
Cellular Response ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Tumor Promoters ◽  
Expression Of Genes ◽  
Molecular Aspects

CCAAT/enhancer-binding proteins (C/EBPs) constitute a family of transcription factors composed of six members that are critical for normal cellular differentiation in a variety of tissues. They promote the expression of genes through interaction with their promoters. Moreover, they have a key role in regulating cellular proliferation through interaction with cell cycle proteins. C/EBPs are considered to be tumor suppressor factors due to their ability to arrest cell growth (contributing to the terminal differentiation of several cell types) and for their role in cellular response to DNA damage, nutrient deprivation, hypoxia, and genotoxic agents. However, C/EBPs can elicit completely opposite effects on cell proliferation and cancer development and they have been described as both tumor promoters and tumor suppressors. This “Janus” role of C/EBPs depends on different factors, such as the type of tumor, the isoform/s expressed in cells, the type of dimerization (homo- or heterodimerization), the presence of inhibitory elements, and the ability to inhibit the expression of other tumor suppressors. In this review, we discuss the implication of the C/EBPs family in cancer, focusing on the molecular aspects that make these transcription factors tumor promoters or tumor suppressors.

scholarly journals NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5902
Author(s):  
Stefan Nagel ◽  
Claudia Pommerenke ◽  
Corinna Meyer ◽  
Hans G. Drexler
Keyword(s):  
Dendritic Cells ◽  
Transcription Factors ◽  
Cell Lines ◽  
Expression Profiling ◽  
Regulatory Network ◽  
Homeobox Gene ◽  
Leukemia Cell Line ◽  
Specific Gene ◽  
Rna Seq ◽  
And Function

Recently, we documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs additionally expressed VENTX. The consequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in an acute myelomonocytic leukemia cell line, MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB, and SPI1 and the CSF-, NOTCH-, and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts on apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2, and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.

scholarly journals RNA-Seq Provides New Insights into the Molecular Events Involved in “Ball-Skin versus Bladder Effect” on Fruit Cracking in Litchi

2021 ◽  
Vol 22 (1) ◽  
pp. 454
Author(s):  
Jun Wang ◽  
Xiao Fang Wu ◽  
Yong Tang ◽  
Jian Guo Li ◽  
Ming Lei Zhao
Keyword(s):  
Transcription Factors ◽  
Plant Hormones ◽  
Fruit Development ◽  
Economic Value ◽  
Lipid Synthesis ◽  
Expression Level ◽  
Agricultural Product ◽  
Rna Seq ◽  
Fruit Cracking ◽  
Molecular Events

Fruit cracking is a disorder of fruit development in response to internal or external cues, which causes a loss in the economic value of fruit. Therefore, exploring the mechanism underlying fruit cracking is of great significance to increase the economic yield of fruit trees. However, the molecular mechanism underlying fruit cracking is still poorly understood. Litchi, as an important tropical and subtropical fruit crop, contributes significantly to the gross agricultural product in Southeast Asia. One important agricultural concern in the litchi industry is that some famous varieties with high economic value such as ‘Nuomici’ are susceptible to fruit cracking. Here, the cracking-susceptible cultivar ‘Nuomici’ and cracking-resistant cultivar ‘Huaizhi’ were selected, and the samples including pericarp and aril during fruit development and cracking were collected for RNA-Seq analysis. Based on weighted gene co-expression network analysis (WGCNA) and the “ball-skin versus bladder effect” theory (fruit cracking occurs upon the aril expanding pressure exceeds the pericarp strength), it was found that seven co-expression modules genes (1733 candidate genes) were closely associated with fruit cracking in ‘Nuomici’. Importantly, we propose that the low expression level of genes related to plant hormones (Auxin, Gibberellins, Ethylene), transcription factors, calcium transport and signaling, and lipid synthesis might decrease the mechanical strength of pericarp in ‘Nuomici’, while high expression level of genes associated with plant hormones (Auxin and abscisic acid), transcription factors, starch/sucrose metabolism, and sugar/water transport might increase the aril expanding pressure, thereby resulting in fruit cracking in ‘Nuomici’. In conclusion, our results provide comprehensive molecular events involved in the “ball-skin versus bladder effect” on fruit cracking in litchi.

MGA2 and SPT23 Are Modifiers of Transcriptional Silencing in Yeast

Genetics ◽  
2000 ◽  
Vol 156 (3) ◽  
pp. 933-941 ◽  
Author(s):  
Mary Lou Dula ◽  
Scott G Holmes
Keyword(s):  
Transcription Factors ◽  
Chromatin Structure ◽  
Transcriptional Control ◽  
Transcriptional Silencing ◽  
Sir Proteins

Abstract Transcriptional silencing at the HM loci and telomeres in yeast depends on several trans-acting factors, including Rap1p and the Sir proteins. The SUM1-1 mutation was identified by its ability to restore silencing to strains deficient in one or more of these trans-acting factors. The mechanism by which SUM1-1 bypasses the requirement for silencing proteins is not known. We identified four loci that when reduced in dosage in diploid strains increase the ability of SUM1-1 strains to suppress silencing defects. Two of the genes responsible for this effect were found to be MGA2 and SPT23. Mga2p and Spt23p were previously identified as functionally related transcription factors that influence chromatin structure. We find that deletion of MGA2 or SPT23 also increases the efficiency of silencing in haploid SUM1-1 strains. These results suggest that Mga2p and Spt23p are antagonists of silencing. Consistent with this proposal we find that deletion of MGA2 or SPT23 also suppresses the silencing defects caused by deletion of the SIR1 gene or by mutations in the HMR silencer sequences. However, we find that Mga2p and Spt23p can positively affect silencing in other contexts; deletion of either MGA2 or SPT23 decreases mating in strains bearing mutations in the HML-E silencer. Mga2p and Spt23p appear to be a novel class of factors that influence disparate pathways of transcriptional control by chromatin.

Transcriptional Control of Parturition: Insights from Gene Regulation Studies in the Myometrium

2021 ◽  
Author(s):  
Nawrah Khader ◽  
Virlana M Shchuka ◽  
Oksana Shynlova ◽  
Jennifer A Mitchell
Keyword(s):  
Transcription Factors ◽  
Regulatory Networks ◽  
Transcriptional Control ◽  
Progesterone Receptors ◽  
Activator Protein 1 ◽  
Transcriptional Regulatory Networks ◽  
Regulatory Pathways ◽  
Transcriptional Regulatory ◽  
Mechanistic Basis ◽  
Labour Onset

Abstract The onset of labour is a culmination of a series of highly coordinated and preparatory physiological events that take place throughout the gestational period. In order to produce the associated contractions needed for fetal delivery, smooth muscle cells in the muscular layer of the uterus (i.e. myometrium) undergo a transition from quiescent to contractile phenotypes. Here, we present the current understanding of the roles transcription factors play in critical labour-associated gene expression changes as part of the molecular mechanistic basis for this transition. Consideration is given to both transcription factors that have been well-studied in a myometrial context, i.e. activator protein 1 (AP-1), progesterone receptors (PRs), estrogen receptors (ERs), and nuclear factor kappa B (NF-κB), as well as additional transcription factors whose gestational event-driving contributions have been demonstrated more recently. These transcription factors may form pregnancy- and labour- associated transcriptional regulatory networks in the myometrium to modulate the timing of labour onset. A more thorough understanding of the transcription factor-mediated, labour-promoting regulatory pathways holds promise for the development of new therapeutic treatments that can be used for the prevention of preterm labour in at-risk women.

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