Study on the effect of regulation of Cordyceps militaris polypeptide on the immune function of mice based on a transcription factor regulatory network

The molecular mechanism of the regulatory effed of schizandrol A (SA) on the immune function of cyclophosphamide-induced immunosuppressive mice was explored in this study. On the basis of 1619 differentially expressed genes related to the regulatory effect of SA on the immune function of mice screened in our previous study, transcription factors and their corresponding target genes were screened in the Transcriptional Regulatory Element Database (TRED), and a transcription factor target gene regulatory network was constructed. The key nodes of the network were statistically analyzed to clarify the role of transcription factors in the regulatory network. The correlation of network genes with diseases was analyzed with an online annotation tool through the Database for Annotation, Visualization and Integrated Discovery (DAVID). Finally, the key factors related to the regulatory effect of SA on the immune function of mice were screened and verified by animal experiments and the detection of related protein expression by western blot analysis. The results showed that SA could alleviate the immunosuppression induced by cyclophosphamide in mice and regulate the protein expression of Jun, Trp53, and Creb1 in the spleen tissue of mice, together with the transcription factors Atf4 and E2f2. SA may thus play a role in the alleviation of some immunity-related diseases (such as cancer) by regulating the immune function of mice through multiple genes and their transcription factors.

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Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22158193 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8193

Author(s):

Daniel Pérez-Cremades ◽

Ana B. Paes ◽

Xavier Vidal-Gómez ◽

Ana Mompeón ◽

Carlos Hermenegildo ◽

...

Keyword(s):

Endothelial Cells ◽

Transcription Factor ◽

Transcription Factors ◽

Regulatory Network ◽

Mirna Target ◽

Target Genes ◽

Functional Characterization ◽

Human Endothelial Cells ◽

Mrna Targets ◽

Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

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Class I TCP transcription factors regulate trichome branching and cuticle development in Arabidopsis

Journal of Experimental Botany ◽

10.1093/jxb/eraa257 ◽

2020 ◽

Vol 71 (18) ◽

pp. 5438-5453

Author(s):

Alejandra Camoirano ◽

Agustín L Arce ◽

Federico D Ariel ◽

Antonela L Alem ◽

Daniel H Gonzalez ◽

...

Keyword(s):

Arabidopsis Thaliana ◽

Transcription Factor ◽

Transcription Factors ◽

Regulatory Network ◽

Class I ◽

Branch Number ◽

Plant Organ ◽

Cuticle Formation ◽

Cuticle Development ◽

Different Levels

Abstract Trichomes and the cuticle are two specialized structures of the aerial epidermis that are important for plant organ development and interaction with the environment. In this study, we report that Arabidopsis thaliana plants affected in the function of the class I TEOSINTE BRANCHED 1, CYCLOIDEA, PCF (TCP) transcription factors TCP14 and TCP15 show overbranched trichomes in leaves and stems and increased cuticle permeability. We found that TCP15 regulates the expression of MYB106, a MIXTA-like transcription factor involved in epidermal cell and cuticle development, and overexpression of MYB106 in a tcp14 tcp15 mutant reduces trichome branch number. TCP14 and TCP15 are also required for the expression of the cuticle biosynthesis genes CYP86A4, GPAT6, and CUS2, and of SHN1 and SHN2, two AP2/EREBP transcription factors required for cutin and wax biosynthesis. SHN1 and CUS2 are also targets of TCP15, indicating that class I TCPs influence cuticle formation acting at different levels, through the regulation of MIXTA-like and SHN transcription factors and of cuticle biosynthesis genes. Our study indicates that class I TCPs are coordinators of the regulatory network involved in trichome and cuticle development.

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Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities

Genome Medicine ◽

10.1186/s13073-020-00799-2 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Juha Mehtonen ◽

Susanna Teppo ◽

Mari Lahnalampi ◽

Aleksi Kokko ◽

Riina Kaukonen ◽

...

Keyword(s):

Bone Marrow ◽

Transcription Factor ◽

Transcription Factors ◽

Regulatory Network ◽

Leukemic Cell ◽

Immune Microenvironment ◽

Ets Transcription Factors ◽

Lineage Differentiation ◽

B Lineage

Abstract Background Tight regulatory loops orchestrate commitment to B cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention. Methods We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion. Results We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment resistance, we show that inhibition of ETS-transcription factors reduced cell viability and resolved pathways contributing to this using scRNA-seq. Conclusions Our data provide a detailed picture of the transcription factor activities characterizing both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1 positive pediatric leukemia identifies drug-targetable transcription factor activities

10.1101/2020.05.27.116293 ◽

2020 ◽

Cited By ~ 2

Author(s):

Juha Mehtonen ◽

Susanna Teppo ◽

Mari Lahnalampi ◽

Aleksi Kokko ◽

Riina Kaukonen ◽

...

Keyword(s):

Bone Marrow ◽

Transcription Factor ◽

Transcription Factors ◽

Regulatory Network ◽

Leukemic Cell ◽

Immune Microenvironment ◽

Ets Transcription Factors ◽

Lineage Differentiation ◽

B Lineage

AbstractTight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention.We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion.We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability.Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.

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Genomic Retargeting of Tumor Suppressors p53 and CTCF Promotes Oncogenesis

10.1101/703124 ◽

2019 ◽

Author(s):

Michal Schwartz ◽

Avital Sarusi Portugez ◽

Bracha Zukerman Attia ◽

Miriam Tannenbaum ◽

Olga Loza ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Tumor Suppressors ◽

Regulatory Network ◽

Regulatory Elements ◽

Cancer Development ◽

Chromatin Binding ◽

Transcriptional Reprogramming ◽

Major Variation ◽

Regulatory Landscape

AbstractGene transcription is substantially regulated by distant regulatory elements via combinatorial binding of transcription factors. It is more and more recognized that alterations in chromatin state and transcription factor binding in these distant regulatory elements may have key roles in cancer development. Here we focused on the first stages of oncogene induced carcinogenic transformation, and characterized the regulatory network underlying transcriptional reprogramming associated with this process. Using Hi-C data, we couple between differentially expressed genes and their differentially active regulatory elements and reveal two candidate transcription factors, p53 and CTCF, as major determinants of transcriptional reprogramming at early stages of HRas-induced transformation. Strikingly, the malignant transcriptional reprograming is promoted by redistribution of chromatin binding of these factors without major variation in their expression level. Our results demonstrate that alterations in the regulatory landscape have a major role in driving oncogene-induced transcriptional reprogramming.

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Reconstruction of a Global Transcriptional Regulatory Network for Control of Lipid Metabolism in Yeast by Using Chromatin Immunoprecipitation with Lambda Exonuclease Digestion

mSystems ◽

10.1128/msystems.00215-17 ◽

2018 ◽

Vol 3 (4) ◽

Cited By ~ 14

Author(s):

David Bergenholm ◽

Guodong Liu ◽

Petter Holland ◽

Jens Nielsen

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Lipid Metabolism ◽

Chromatin Immunoprecipitation ◽

Regulatory Network ◽

Regulatory Networks ◽

Transcriptional Regulatory Network ◽

Lambda Exonuclease ◽

Transcriptional Regulatory ◽

Exonuclease Digestion

ABSTRACT To build transcription regulatory networks, transcription factor binding must be analyzed in cells grown under different conditions because their responses and targets differ depending on environmental conditions. We performed whole-genome analysis of the DNA binding of five Saccharomyces cerevisiae transcription factors involved in lipid metabolism, Ino2, Ino4, Hap1, Oaf1, and Pip2, in response to four different environmental conditions in chemostat cultures, which allowed us to keep the specific growth rate constant. Chromatin immunoprecipitation with lambda exonuclease digestion (ChIP-exo) enabled the detection of binding events at a high resolution. We discovered a large number of unidentified targets and thus expanded functions for each transcription factor (e.g., glutamate biosynthesis as a target of Oaf1 and Pip2). Moreover, condition-dependent binding of transcription factors in response to cell metabolic state (e.g., differential binding of Ino2 between fermentative and respiratory metabolic conditions) was clearly suggested. Combining the new binding data with previously published data from transcription factor deletion studies revealed the high complexity of the transcriptional regulatory network for lipid metabolism in yeast, which involves the combinatorial and complementary regulation by multiple transcription factors. We anticipate that our work will provide insights into transcription factor binding dynamics that will prove useful for the understanding of transcription regulatory networks. IMPORTANCE Transcription factors play a crucial role in the regulation of gene expression and adaptation to different environments. To better understand the underlying roles of these adaptations, we performed experiments that give us high-resolution binding of transcription factors to their targets. We investigated five transcription factors involved in lipid metabolism in yeast, and we discovered multiple novel targets and condition-specific responses that allow us to draw a better regulatory map of the lipid metabolism.

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Regulation of transcription reactivation dynamics exiting mitosis

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009354 ◽

2021 ◽

Vol 17 (10) ◽

pp. e1009354

Author(s):

Sergio Sarnataro ◽

Andrea Riba ◽

Nacho Molina

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Transcription Factor ◽

Transcription Factors ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Control Cell ◽

Core Gene ◽

Regulation Of Transcription ◽

Gene Regulatory

Proliferating cells experience a global reduction of transcription during mitosis, yet their cell identity is maintained and regulatory information is propagated from mother to daughter cells. Mitotic bookmarking by transcription factors has been proposed as a potential mechanism to ensure the reactivation of transcription at the proper set of genes exiting mitosis. Recently, mitotic transcription and waves of transcription reactivation have been observed in synchronized populations of human hepatoma cells. However, the study did not consider that mitotic-arrested cell populations progressively desynchronize leading to measurements of gene expression on a mixture of cells at different internal cell-cycle times. Moreover, it is not well understood yet what is the precise role of mitotic bookmarking on mitotic transcription as well as on the transcription reactivation waves. Ultimately, the core gene regulatory network driving the precise transcription reactivation dynamics remains to be identified. To address these questions, we developed a mathematical model to correct for the progressive desynchronization of cells and estimate gene expression dynamics with respect to a cell-cycle pseudotime. Furthermore, we used a multiple linear regression model to infer transcription factor activity dynamics. Our analysis allows us to characterize waves of transcription factor activities exiting mitosis and predict a core gene regulatory network responsible of the transcription reactivation dynamics. Moreover, we identified more than 60 transcription factors that are highly active during mitosis and represent new candidates of mitotic bookmarking factors which could be relevant therapeutic targets to control cell proliferation.

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A Protein Moonlighting Based Model to Reveal Transcription Factor Druggability for Prostate Carcinoma

10.21203/rs.3.rs-318403/v1 ◽

2021 ◽

Author(s):

Sagnik Sen ◽

Ashmita Dey ◽

Ujjwal Maulik

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Cancer Progression ◽

Prostate Carcinoma ◽

Regulatory Network ◽

Drug Targeting ◽

The United States ◽

Dynamic Nature ◽

Feed Forward ◽

Feed Forward Loop

Abstract BackgroundProstate cancer is the second leading cause of cancer-related death in men in the United States. Metastasis shows poor survival even though the recovery rate is high. In spite of numerous studies regarding prostate carcinoma, multiple questions are stilled unanswered. In this regards, gene regulatory network can uncover the mechanisms behind cancer progression, and metastasis. In the regulatory network, among the three prime molecular members, transcription factors and microRNAs are known for their regulatory activity where transcription factor can target both microRNAs and genes. Under a feed forward loop, transcription factors can be a good druggable candidate. However, due to the dynamic nature of transcription factors, designing an appropriate drug becomes challenging.ResultWe have proposed a computational model to study the uncertainty of transcription factors and suggest the appropriate cellular conditions for drug targeting. We have selected feed-forward loops depending on the shared list of the functional annotations among transcription factors, genes, and miRNAs. From the potential feed forward loop cores, six transcription factors were identified as druggable targets, which include AR, CEBPB, CREB1, ETS1, NFKB1, and RELA. The selected transcription factors have been investigated based on the evolutionary co-variance study, post-translation modifications, and disordered region identification. The structural unrest of the selected transcription factors can be observed from outcomes. Comparing the results of the aforementioned analyses, probable binding clefts have also been identified. transcription factors are known for their Protein Moonlighting properties, which provide unrelated multi-functionalities within the same or different subcellular localizations. Following that, we have identified such functions that are suitable for drug targeting. Finally, we have tried to identify membraneless organelles for providing more specificity to the proposed time and space theory.ConclusionThe study has provided certain possibilities on TF based therapeutics. The controlled dynamic nature of the TF may have enhanced the chances where TFs can be consider as one of the prime drug targets. The usual presence of TF at nucleus cannot explain its functional multiplicity whereas nucleus speckles can help to explain it. Finally, the combination of membranless phase separation and protein moonlighting has provided possible druggable period within the biological clock.

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Genome-Wide Mapping of Binding Sites Reveals Multiple Biological Functions of the Transcription Factor Cst6p in Saccharomyces cerevisiae

mBio ◽

10.1128/mbio.00559-16 ◽

2016 ◽

Vol 7 (3) ◽

Cited By ~ 9

Author(s):

Guodong Liu ◽

David Bergenholm ◽

Jens Nielsen

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Transcription Factors ◽

Binding Sites ◽

Regulatory Network ◽

Deletion Mutant ◽

Transcriptional Regulatory Network ◽

Biological Processes ◽

Genome Wide ◽

Transcriptional Regulatory

ABSTRACT In the model eukaryote Saccharomyces cerevisiae , the transcription factor Cst6p has been reported to play important roles in several biological processes. However, the genome-wide targets of Cst6p and its physiological functions remain unknown. Here, we mapped the genome-wide binding sites of Cst6p at high resolution. Cst6p binds to the promoter regions of 59 genes with various biological functions when cells are grown on ethanol but hardly binds to the promoter at any gene when cells are grown on glucose. The retarded growth of the CST6 deletion mutant on ethanol is attributed to the markedly decreased expression of NCE103 , encoding a carbonic anhydrase, which is a direct target of Cst6p. The target genes of Cst6p have a large overlap with those of stress-responsive transcription factors, such as Sko1p and Skn7p. In addition, a CST6 deletion mutant growing on ethanol shows hypersensitivity to oxidative stress and ethanol stress, assigning Cst6p as a new member of the stress-responsive transcriptional regulatory network. These results show that mapping of genome-wide binding sites can provide new insights into the function of transcription factors and highlight the highly connected and condition-dependent nature of the transcriptional regulatory network in S. cerevisiae . IMPORTANCE Transcription factors regulate the activity of various biological processes through binding to specific DNA sequences. Therefore, the determination of binding positions is important for the understanding of the regulatory effects of transcription factors. In the model eukaryote Saccharomyces cerevisiae , the transcription factor Cst6p has been reported to regulate several biological processes, while its genome-wide targets remain unknown. Here, we mapped the genome-wide binding sites of Cst6p at high resolution. We show that the binding of Cst6p to its target promoters is condition dependent and explain the mechanism for the retarded growth of the CST6 deletion mutant on ethanol. Furthermore, we demonstrate that Cst6p is a new member of a stress-responsive transcriptional regulatory network. These results provide deeper understanding of the function of the dynamic transcriptional regulatory network in S. cerevisiae .

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