scholarly journals BET Bromodomain Inhibitors Target the NEUROD1-subtype SCLC by Blocking NEUROD1 Transactivation

2021 ◽  
Author(s):  
Haobin Chen ◽  
Lisa Gesumaria ◽  
Young-Kwon Park ◽  
Trudy G Oliver ◽  
Dinah S. Singer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Molecular Subtypes ◽  
Integrated Analysis ◽  
Gene Promoters ◽  
Rna Seq ◽  
New Approach ◽  
Dismal Prognosis ◽  
Precision Therapy ◽  
Bromodomain Proteins

SCLC is a recalcitrant malignancy with a dismal prognosis. Four molecular subtypes of SCLC have been named, each associated with one master transcription factor (ASCL1, NEUROD1, POU2F3, or YAP1). Much is still unknown about the function and transactivation of NEUROD1 in this malignancy. Herein we report that knockout of NEUROD1 triggered SCLC to evolve into a YAP1 subtype. Through an integrated analysis of RNA-seq and ChIP-seq, we found NEUROD1 regulates neural-related genes by binding to gene promoters and distal enhancers. NEUROD1 physically interacts with BET bromodomain proteins and recruits them to actively transcribed genes. Inhibition of BET bromodomain proteins blocks NEUROD1 transactivation and suppresses SCLC growth. We identified LSAMP as one of the NEUROD1-target genes that mediate SCLC sensitivity to BET bromodomain inhibitors. Our findings suggest that targeting transcriptional coactivators could be a new approach to block master transcription factors in SCLC to enable precision therapy.

scholarly journals The Wheat GENIE3 Network Provides Biologically-Relevant Information in Polyploid Wheat

2020 ◽  
Vol 10 (10) ◽  
pp. 3675-3686 ◽  
Author(s):  
Sophie A. Harrington ◽  
Anna E. Backhaus ◽  
Ajit Singh ◽  
Keywan Hassani-Pak ◽  
Cristobal Uauy
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Candidate Gene ◽  
Web Application ◽  
Regulatory Networks ◽  
Target Genes ◽  
Gene Prediction ◽  
Relevant Information ◽  
Rna Seq ◽  
Biologically Relevant

Gene regulatory networks are powerful tools which facilitate hypothesis generation and candidate gene discovery. However, the extent to which the network predictions are biologically relevant is often unclear. Recently a GENIE3 network which predicted targets of wheat transcription factors was produced. Here we used an independent RNA-Seq dataset to test the predictions of the wheat GENIE3 network for the senescence-regulating transcription factor NAM-A1 (TraesCS6A02G108300). We re-analyzed the RNA-Seq data against the RefSeqv1.0 genome and identified a set of differentially expressed genes (DEGs) between the wild-type and nam-a1 mutant which recapitulated the known role of NAM-A1 in senescence and nutrient remobilisation. We found that the GENIE3-predicted target genes of NAM-A1 overlap significantly with the DEGs, more than would be expected by chance. Based on high levels of overlap between GENIE3-predicted target genes and the DEGs, we identified candidate senescence regulators. We then explored genome-wide trends in the network related to polyploidy and found that only homeologous transcription factors are likely to share predicted targets in common. However, homeologs which vary in expression levels across tissues are less likely to share predicted targets than those that do not, suggesting that they may be more likely to act in distinct pathways. This work demonstrates that the wheat GENIE3 network can provide biologically-relevant predictions of transcription factor targets, which can be used for candidate gene prediction and for global analyses of transcription factor function. The GENIE3 network has now been integrated into the KnetMiner web application, facilitating its use in future studies.

The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain

Development ◽  
1991 ◽  
Vol 113 (4) ◽  
pp. 1093-1104 ◽  
Author(s):  
D. Lazzaro ◽  
M. Price ◽  
M. de Felice ◽  
R. Di Lauro
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Bronchial Epithelium ◽  
Specific Gene ◽  
Thyroid Cell ◽  
Gene Promoters ◽  
Specific Expression ◽  
Rat Thyroid ◽  
Endodermal Cells ◽  
The Brain

TTF-1, a homeodomain-containing transcription factor, which is required for the specific expression of the thyroglobulin and thyroperoxidase gene promoters in differentiated thyroid cell lines, is expressed at the very beginning of rat thyroid differentiation. TTF-1 mRNA is detected in the endodermal cells of the thyroid rudiment in the rat embryo and precedes the expression of the two known target genes by 5 days. No delay is observed between the appearance of TTF-1 mRNA and protein, which shows a clear nuclear localization. In the adult thyroid, TTF-1 is present only in the endoderm-derived follicular cells. Two additional domains of expression of TTF-1 have been observed, the lung and restricted areas of the brain. In the lung, TTF-1 mRNA and protein are also present at the earliest stages of differentiation and are later confined to the bronchial epithelium. In the brain, TTF-1 appears to be restricted to structures of diencephalic origin, including the developing neurohypophysis. The early detection of TTF-1 in the endodermal cells of the thyroid and lung anlage and in restricted neuroblast populations indicates that TTF-1 may have a role in cell determination in these three systems and that additional mechanisms may be involved in the activation of thyroid-specific gene expression.

scholarly journals Integrated Analysis of lncRNA and mRNA Reveals Novel Insights into Wool Bending in Zhongwei Goat

Animals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3326
Author(s):  
Xiaobo Li ◽  
Zhanfa Liu ◽  
Shaohui Ye ◽  
Yue Liu ◽  
Qian Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Economic Value ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Hair Follicles ◽  
Functional Enrichment ◽  
Integrated Analysis ◽  
Rna Seq ◽  
Camp Signaling Pathway

Chinese Zhongwei goat is a rare and precious fur breed as its lamb fur is a well-known fur product. Wool bending of lamb fur of the Zhongwei goat is its most striking feature. However, the curvature of the wool decreases gradually with growth, which significantly affects its quality and economic value. The mechanism regulating the phenotypic changes of hair bending is still unclear. In the present study, the skin tissues of Zhongwei goats at 45 days (curving wool) and 108 days (slight-curving wool) after birth were taken as the research objects, and the expression profiling of long non-coding RNAs (lncRNAs) and mRNAs were analyzed based on the Ribo Zero RNA sequencing (RNA-seq) method. In total, 46,013 mRNAs and 13,549 lncRNAs were identified, of which 352 were differentially expressed mRNAs and 60 were. lncRNAs. Functional enrichment analysis of the target genes of lncRNAs were mainly enriched in PI3K-Akt, Arachidonic acid metabolic, cAMP, Wnt, and other signaling pathways. The qRT-PCR results of eight selected lncRNAs and target genes were consistent with the sequencing result, which indicated our data were reliable. Through the analysis of the weighted gene co-expression network, 13 co-expression modules were identified. The turquoise module contained a large number of differential expressed lncRNAs, which were mainly enriched in the PI3K-Akt signaling pathway and cAMP signaling pathway. The predicted LOC102172600 and LOC102191729 might affect the development of hair follicles and the curvature of wool by regulating the target genes. Our study provides novel insights into the potential roles of lncRNAs in the regulation of wool bending. In addition, the study offers a theoretical basis for further study of goat wool growth, so as to be a guidance and reference for breeding and improvement in the future.

Retinoblastoma Protein and the Leukemia-Associated PLZF Transcription Factor Interact To Repress Target Gene Promoters.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1240-1240
Author(s):  
Kevin R. Petrie ◽  
Fabien Guidez ◽  
Jun Zhu ◽  
Gareth Owen ◽  
Yat Peng Chew ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Transcriptional Repression ◽  
Cell Biology ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Gene Promoters ◽  
Cell Commitment

Abstract Translocations of the retinoic acid receptor alpha (RARA) locus with the PLZF or PML genes lead to expression of oncogenic PLZF-RARα or PML-RARα fusion proteins, respectively. These fusion oncoproteins constitutively repress RARα target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARα have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (POZ) and DNA binding (zinc-finger) domains. Additionally, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction between PML or E2F1 with Rb, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. The interaction between PLZF and Rb is further underlined by chromatin immunoprecipitation analysis of PLZF binding to genomic DNA, which shows that PLZF associates with genes controlling cell proliferation known to be regulated by Rb and E2F (for example cdc6). Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to have roles in stem cell biology and, taken together, these data provide a plausible scenario in which interactions between PLZF and Rb function in stem cell commitment or maintenance and self-renewal. The oncogenic PLZF-RARα fusion also interacts with Rb, suggesting that deregulation of Rb function may be a factor in the molecular pathogenesis of PLZF-RARα associated acute promyelocytic leukemia.

scholarly journals Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I

2015 ◽  
Vol 112 (7) ◽  
pp. E677-E686 ◽  
Author(s):  
Rodrigo Peña-Hernández ◽  
Maud Marques ◽  
Khalid Hilmi ◽  
Teijun Zhao ◽  
Amine Saad ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Cellular Response ◽  
Target Genes ◽  
Regulatory Protein ◽  
Metabolic Stress ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
The Impact

CCCTC-binding factor (CTCF) is a key regulator of nuclear chromatin structure and gene regulation. The impact of CTCF on transcriptional output is highly varied, ranging from repression to transcriptional pausing and transactivation. The multifunctional nature of CTCF may be directed solely through remodeling chromatin architecture. However, another hypothesis is that the multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique functions. Consistent with this hypothesis, our mass spectrometry analyses of CTCF interacting partners reveal a previously undefined association with the transcription factor general transcription factor II-I (TFII-I). Biochemical fractionation of CTCF indicates that a distinct CTCF complex incorporating TFII-I is assembled on DNA. Unexpectedly, we found that the interaction between CTCF and TFII-I is essential for directing CTCF to the promoter proximal regulatory regions of target genes across the genome, particularly at genes involved in metabolism. At genes coregulated by CTCF and TFII-I, we find knockdown of TFII-I results in diminished CTCF binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase II phosphorylation at serine 5. Phenotypically, knockdown of TFII-I alters the cellular response to metabolic stress. Our data indicate that TFII-I directs CTCF binding to target genes, and in turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.

scholarly journals Integrated Analysis of MicroRNA and Target Genes in Brachypodium distachyon Infected by Magnaporthe oryzae by Small RNA and Degradome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Weiye Peng ◽  
Na Song ◽  
Wei Li ◽  
Mingxiong Yan ◽  
Chenting Huang ◽  
...  
Keyword(s):  
Magnaporthe Oryzae ◽  
Small Rna ◽  
Target Genes ◽  
Brachypodium Distachyon ◽  
Grass Species ◽  
Integrated Analysis ◽  
Post Inoculation ◽  
New Approach ◽  
Degradome Sequencing ◽  
Differentially Expressed Mirnas

Rice blast caused by Magnaporthe oryzae is one of the most important diseases that seriously threaten rice production. Brachypodium distachyon is a grass species closely related to grain crops, such as rice, barley, and wheat, and has become a new model plant of Gramineae. In this study, 15 small RNA samples were sequenced to examine the dynamic changes in microRNA (miRNA) expression in B. distachyon infected by M. oryzae at 0, 24, and 48 h after inoculation. We identified 432 conserved miRNAs and 288 predicted candidate miRNAs in B. distachyon. Additionally, there were 7 and 19 differentially expressed miRNAs at 24 and 48 h post-inoculation, respectively. Furthermore, using degradome sequencing, we identified 2,126 genes as targets for 308 miRNAs; using quantitative real-time PCR (qRT-PCR), we validated five miRNA/target regulatory units involved in B. distachyon–M. oryzae interactions. Moreover, using co-transformation technology, we demonstrated that BdNAC21 was negatively regulated by miR164c. This study provides a new approach for identifying resistance genes in B. distachyon by mining the miRNA regulatory network of host–pathogen interactions.

scholarly journals Identification of a Distinct miRNA Regulatory Network in the Tumor Microenvironment of Transformed Mycosis Fungoides

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5854
Author(s):  
Cosimo Di Raimondo ◽  
Zhen Han ◽  
Chingyu Su ◽  
Xiwei Wu ◽  
Hanjun Qin ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mrna Expression ◽  
Mycosis Fungoides ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cell Transformation ◽  
Expression Profiles ◽  
Poor Response ◽  
Rna Seq ◽  
Dismal Prognosis

Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20–50% of advanced MF and is generally associated with poor response and dismal prognosis. Although different mechanisms have been proposed to explain the pathogenesis, little is known about the role of microRNAs (miRs) in transcriptional regulation of LCT-MF. Here, we investigated the miR and mRNA expression profile in lesional skin samples of patients with LCT-MF and non-LCT MF using RNA-seq analysis. We found miR-146a and miR-21 to be significantly upregulated, and miR-708 the most significantly downregulated miR in LCT-MF. Integration of miR and mRNA expression profiles revealed the miR-regulated networks in LCT-MF. Ingenuity pathway analysis (IPA) demonstrated the involvement of genes for ICOS-ICOSL, PD1-PDL1, NF-κB, E2F transcription, and molecular mechanisms of cancer signaling pathways. Quantitative real time (qRT)-PCR results of target genes were consistent with the RNA-seq data. We further identified the immunosuppressive tumor microenvironment (TME) in LCT-MF. Moreover, our data indicated that miR-146a, -21 and -708 are associated with the immunosuppressive TME in LCT-MF. Collectively, our results suggest that the key LCT-MF associated miRs and their regulated networks may provide insights into its pathogenesis and identify promising targets for novel therapeutic strategies.

scholarly journals The Scleraxis Transcription Factor Directly Regulates Multiple Distinct Molecular and Cellular Processes During Early Tendon Cell Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Han Liu ◽  
Jingyue Xu ◽  
Yu Lan ◽  
Hee-Woong Lim ◽  
Rulang Jiang
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Seq ◽  
Tendon Cell ◽  
Tendon Development ◽  
Genome Wide ◽  
Direct Target ◽  
Embryonic Tendon

Proper development of tendons is crucial for the integration and function of the musculoskeletal system. Currently little is known about the molecular mechanisms controlling tendon development and tendon cell differentiation. The transcription factor Scleraxis (Scx) is expressed throughout tendon development and plays essential roles in both embryonic tendon development and adult tendon healing, but few direct target genes of Scx in tendon development have been reported and genome-wide identification of Scx direct target genes in vivo has been lacking. In this study, we have generated a ScxFlag knockin mouse strain, which produces fully functional endogenous Scx proteins containing a 2xFLAG epitope tag at the carboxy terminus. We mapped the genome-wide Scx binding sites in the developing limb tendon tissues, identifying 12,097 high quality Scx regulatory cis-elements in-around 7,520 genes. Comparative analysis with previously reported embryonic tendon cell RNA-seq data identified 490 candidate Scx direct target genes in early tendon development. Furthermore, we characterized a new Scx gene-knockout mouse line and performed whole transcriptome RNA sequencing analysis of E15.5 forelimb tendon cells from Scx–/– embryos and control littermates, identifying 68 genes whose expression in the developing tendon tissues significantly depended on Scx function. Combined analysis of the ChIP-seq and RNA-seq data yielded 32 direct target genes that required Scx for activation and an additional 17 target genes whose expression was suppressed by Scx during early tendon development. We further analyzed and validated Scx-dependent tendon-specific expression patterns of a subset of the target genes, including Fmod, Kera, Htra3, Ssc5d, Tnmd, and Zfp185, by in situ hybridization and real-time quantitative polymerase chain reaction assays. These results provide novel insights into the molecular mechanisms mediating Scx function in tendon development and homeostasis. The ChIP-seq and RNA-seq data provide a rich resource for aiding design of further studies of the mechanisms regulating tendon cell differentiation and tendon tissue regeneration. The ScxFlag mice provide a valuable new tool for unraveling the molecular mechanisms involving Scx in the protein interaction and gene-regulatory networks underlying many developmental and disease processes.

scholarly journals Permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver

2021 ◽  
Author(s):  
Anjana Ramdas Nair ◽  
Priyanka Lakhiani ◽  
Chi Zhang ◽  
Filippo Macchi ◽  
Kirsten C. Sadler
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Expression Patterns ◽  
Transcriptional Response ◽  
Differentially Expressed ◽  
Small Subset ◽  
Gene Promoters ◽  
Transcriptional Responses ◽  
Functional Studies ◽  
Activating Transcription Factor

ABSTRACTProteostatic stress initiates a transcriptional response that is unique to the stress condition, yet the regulatory mechanisms underlying the distinct gene expression patterns observed in stressed cells remains unknown. Using a functional genomic approach, we investigated how activating transcription factor 6 (ATF6), a key transcription factor in the unfolded protein response (UPR), regulates target genes. We first designed a computational strategy to define Atf6 target genes based on the evolutionary conservation of predicted ATF6 binding in gene promoters, identifying 652 conserved putative Atf6 target (CPAT) genes. CPATs were overrepresented for genes functioning in the UPR, however, the majority functioned in cellular processes unrelated to proteostasis, including small molecule metabolism and development. Functional studies of stress-independent and toxicant based Atf6 activation in zebrafish livers showed that the pattern of CPAT expression in response to Atf6 overexpression, alcohol and arsenic was unique. Only 34 CPATs were differentially expressed in all conditions, indicating that Atf6 is sufficient to regulate a small subset of CPATs. Blocking Atf6 using Ceapins in zebrafish demonstrated that Atf6 is necessary for activation of these genes in response to arsenic. We investigated CPAT during physiologically mediated hepatocyte stress using liver regeneration in mice as a model. Over half of all CPATs were differentially expressed during this process. This was attributed to the permissive chromatin environment in quiescent livers on the promoters of these genes, characterized by the absence of H3K27me3 and enrichment of H3K4me3. Taken together, these data uncover a complex transcriptional response to Atf6 activation and implicate a permissive epigenome as a mechanism by which distinct transcriptional responses are regulated by Atf6.

scholarly journals Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response

Gut ◽  
2019 ◽  
Vol 69 (1) ◽  
pp. 18-31 ◽  
Author(s):  
Ruiping Wang ◽  
Shumei Song ◽  
Kazuto Harada ◽  
Fatemeh Ghazanfari Amlashi ◽  
Brian Badgwell ◽  
...  
Keyword(s):  
T Cell ◽  
Gastric Adenocarcinoma ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Molecular Subtypes ◽  
Integrated Analysis ◽  
Rna Seq ◽  
Response To Chemotherapy ◽  
Novel Targets

ObjectivePeritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC’s development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.DesignWe performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.ResultsWe identified distinct alterations in PC versus primary GACs, such as more frequentCDH1 and TAF1mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations inTP53, CDH1, TAF1andKMT2C, higher level of ‘clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ‘mesenchymal-like’ and ‘epithelial-like’ with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive ‘mesenchymal-like’ subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.ConclusionsWe have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.

Sign in / Sign up

Export Citation Format

Share Document