Systems-level identification of transcription factors critical for mouse embryonic development

AbstractDynamic changes in the transcriptional regulatory circuit can influence the specification of distinct cell types. Numerous transcription factors (TFs) have been shown to function through dynamic rewiring during embryonic development but a comprehensive survey on the global regulatory network is still lacking. Here, we performed an integrated analysis of epigenomic and transcriptomic data to reveal key regulators from 2 cells to postnatal day 0 in mouse embryogenesis. We predicted 3D chromatin interactions including enhancer-promoter interactions in 12 tissues across 8 developmental stages, which facilitates linking TFs to their target genes for constructing genetic networks. To identify driver TFs particularly those not necessarily differentially expressed ones, we developed a new algorithm, dubbed as Taiji, to assess the global importance of TFs in development. Through comparative analysis across tissues and developmental stages, we systematically uncovered TFs that are critical for lineage-specific and stage-dependent tissue specification. Most interestingly, we have identified TF combinations that function in spatiotemporal order to form transcriptional waves regulating developmental progress and differentiation. Not only does our analysis provide the first comprehensive map of transcriptional regulatory circuits during mouse embryonic development, the identified novel regulators and the predicted 3D chromatin interactions also provide a valuable resource to guide further mechanistic studies.

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Taiji: System-level identification of key transcription factors reveals transcriptional waves in mouse embryonic development

Science Advances ◽

10.1126/sciadv.aav3262 ◽

2019 ◽

Vol 5 (3) ◽

pp. eaav3262 ◽

Cited By ~ 7

Author(s):

Kai Zhang ◽

Mengchi Wang ◽

Ying Zhao ◽

Wei Wang

Keyword(s):

Transcription Factors ◽

Embryonic Development ◽

Regulatory Networks ◽

Target Genes ◽

Developmental Stages ◽

Three Dimensional ◽

Cell Types ◽

System Level ◽

Transcriptional Regulatory Networks ◽

Developmental Progress

Transcriptional regulation is pivotal to the specification of distinct cell types during embryonic development. However, it still lacks a systematic way to identify key transcription factors (TFs) orchestrating the temporal and tissue specificity of gene expression. Here, we integrated epigenomic and transcriptomic data to reveal key regulators from two cells to postnatal day 0 in mouse embryogenesis. We predicted three-dimensional chromatin interactions in 12 tissues across eight developmental stages, which facilitates linking TFs to their target genes for constructing transcriptional regulatory networks. To identify driver TFs, we developed a new algorithm, dubbed Taiji, to assess the global influence of each TF and systematically uncovered TFs critical for lineage-specific and stage-dependent tissue specification. We have also identified TF combinations that function in spatiotemporal order to form transcriptional waves regulating developmental progress. Furthermore, lacking stage-specific TF combinations suggests a distributed timing strategy to orchestrate the coordination between tissues during embryonic development.

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Screening Driving Transcription Factors in the Processing of Gastric Cancer

Gastroenterology Research and Practice ◽

10.1155/2016/8431480 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Guangzhong Xu ◽

Kai Li ◽

Nengwei Zhang ◽

Bin Zhu ◽

Guosheng Feng

Keyword(s):

Gastric Cancer ◽

Transcription Factors ◽

Regulatory Network ◽

Target Genes ◽

Transcriptional Regulatory Network ◽

Expression Profiles ◽

Functional Enrichment ◽

Regulatory Mechanisms ◽

Integrated Analysis ◽

Transcriptional Regulatory

Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer.Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed.Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls), a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer.Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

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Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting protein

Genes & Development ◽

10.1101/gad.14.14.1741 ◽

2000 ◽

Vol 14 (14) ◽

pp. 1741-1749 ◽

Cited By ~ 1

Author(s):

Ken-ichi Tago ◽

Tsutomu Nakamura ◽

Michiru Nishita ◽

Junko Hyodo ◽

Shin-ichi Nagai ◽

...

Keyword(s):

Cell Proliferation ◽

Transcription Factors ◽

Embryonic Development ◽

Wnt Signaling ◽

Signaling Pathway ◽

Target Genes ◽

Wnt Signaling Pathway ◽

Axis Formation ◽

Interacting Protein

Wnt signaling has an important role in both embryonic development and tumorigenesis. β-Catenin, a key component of the Wnt signaling pathway, interacts with the TCF/LEF family of transcription factors and activates transcription of Wnt target genes. Here, we identify a novel β-catenin-interacting protein, ICAT, that was found to inhibit the interaction of β-catenin with TCF-4 and represses β-catenin–TCF-4-mediated transactivation. Furthermore, ICAT inhibited Xenopus axis formation by interfering with Wnt signaling. These results suggest that ICAT negatively regulates Wnt signaling via inhibition of the interaction between β-catenin and TCF and is integral in development and cell proliferation.

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Identification of pathogenic genes and transcription factors in respiratory syncytial virus

BMC Pediatrics ◽

10.1186/s12887-020-02480-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lei Li ◽

Yong An Ni ◽

Zhenfeng Song ◽

Zhi Yi ◽

Fang Wang

Keyword(s):

Transcription Factors ◽

Respiratory Syncytial Virus ◽

Respiratory Infections ◽

Transcriptional Regulatory Network ◽

Enrichment Analysis ◽

Microarray Dataset ◽

Integrated Analysis ◽

Pathogenic Genes ◽

Transcriptional Regulatory ◽

Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infections in children, especially bronchiolitis. Our study aimed to identify the key genes and upstream transcription factors in RSV. Methods To screen for RSV pathogenic genes, an integrated analysis was performed using the RSV microarray dataset in GEO. Functional annotation and potential pathways for differentially expressed genes (DEGs) were further explored by GO and KEGG enrichment analysis. We constructed the RSV-specific transcriptional regulatory network to identify key transcription factors for DEGs in RSV. Results From three GEO datasets, we identified 1059 DEGs (493 up-regulated and 566 down-regulated genes, FDR < 0.05 and |Combined.ES| > 0.8) between RSV patients and normal controls. GO and KEGG analysis revealed that ‘response to virus’ (FDR = 7.13E-15), ‘mitochondrion’ (FDR = 1.39E-14) and ‘Asthma’ (FDR = 1.28E-06) were significantly enriched pathways for DEGs. The expression of IFI27, IFI44, IFITM3, FCER1A, and ISG15 were shown to be involved in the pathogenesis of RSV. Conclusions We concluded that IFI27, IFI44, IFITM3, FCER1A, and ISG15 may play a role in RSV. Our finding may contribute to the development of new potential biomarkers, reveal the underlying pathogenesis and also identify novel therapeutic targets for RSV.

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CT-FOCS: a novel method for inferring cell type-specific enhancer-promoter maps

10.1101/707158 ◽

2019 ◽

Author(s):

Tom Aharon Hait ◽

Ran Elkon ◽

Ron Shamir

Keyword(s):

Gene Expression ◽

Target Genes ◽

Expression Patterns ◽

Cell Types ◽

Specific Gene ◽

Cell Type ◽

Chromatin Interactions ◽

Cell Type Specific ◽

Novel Method ◽

Validation Scheme

AbstractSpatiotemporal gene expression patterns are governed to a large extent by enhancer elements, typically located distally from their target genes. Identification of enhancer-promoter (EP) links that are specific and functional in individual cell types is a key challenge in understanding gene regulation. We introduce CT-FOCS, a new statistical inference method that utilizes multiple replicates per cell type to infer cell type-specific EP links. Computationally predicted EP links are usually benchmarked against experimentally determined chromatin interactions measured by ChIA-PET and promoter-capture HiC techniques. We expand this validation scheme by using also loops that overlap in their anchor sites. In analyzing 1,366 samples from ENCODE, Roadmap epigenomics and FANTOM5, CT-FOCS inferred highly cell type-specific EP links more accurately than state-of-the-art methods. We illustrate how our inferred EP links drive cell type-specific gene expression and regulation.

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Regulation of cellular iron metabolism

Biochemical Journal ◽

10.1042/bj20101825 ◽

2011 ◽

Vol 434 (3) ◽

pp. 365-381 ◽

Cited By ~ 505

Author(s):

Jian Wang ◽

Kostas Pantopoulos

Keyword(s):

Iron Metabolism ◽

Mammalian Cells ◽

Regulatory Protein ◽

Cell Types ◽

Excess Iron ◽

Cellular Iron ◽

System A ◽

Regulatory Circuit ◽

Transcriptional Regulatory ◽

Responsive Element

Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.

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Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

10.1101/856559 ◽

2019 ◽

Author(s):

Peng Gao ◽

Changya Chen ◽

Elizabeth D. Howell ◽

Yan Li ◽

Joanna Tober ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Hematopoietic Stem Cells ◽

Developmental Stage ◽

Regulatory Networks ◽

Developmental Stages ◽

Hemogenic Endothelium ◽

Hematopoietic Stem ◽

Transcriptional Regulatory ◽

Computational Analyses

AbstractHematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-Seq and histone mark ChIP-Seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in the mouse. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries (dorsal aorta, umbilical and vitelline), an enriched population of pre-hematopoietic stem cells (pre-HSCs), fetal liver HSCs, and adult bone marrow HSCs. We observed dynamic and combinatorial epigenetic changes that mark regulatory DNA sequences including gene promoters and enhancers. Using epigenetic signatures, we identified enhancers for each developmental stage. Only 12% of enhancers are primed, and 78% are active, suggesting the vast majority of enhancers are established de novo at the developmental stages where they are required to control their target genes, without prior priming in earlier stages. We constructed developmental-stage-specific transcriptional regulatory networks during HSC ontogeny by linking enhancers and predicted bound transcription factors to their target promoters using a novel computational algorithm. Our computational analyses predicted known transcriptional regulators for the endothelial-to-hematopoietic transition, validating our overall approach, and identified putative novel transcription factors whose regulon activities correlate with the emergence of pre-HSCs. We validated roles for the broadly expressed transcription factors SP3 and MAZ in arterial hemogenic endothelium. Our data and computational analyses provide a useful resource for uncovering regulators of HSC formation.

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Genomic features of BRDT binding sites in gene units suggest transcriptional partners and specific epigenetic landscapes to regulate transcriptional activity during spermatogenesis

10.1101/822874 ◽

2019 ◽

Author(s):

Li Wang ◽

Iouri Chepelev ◽

Yoon Ra Her ◽

Marcia Manterola ◽

Binyamin Berkovits ◽

...

Keyword(s):

Transcription Factors ◽

Binding Sites ◽

Target Genes ◽

Germ Line ◽

Cell Types ◽

Histone Variants ◽

Wide Distribution ◽

Male Meiosis ◽

Downstream Target ◽

Pachytene Spermatocytes

AbstractBRDT, a member of the BET family of double bromodomain-containing proteins, is expressed uniquely in the male germ line, is essential for spermatogenesis in the mouse, and binds to acetylated transcription start sites of genes expressed in meiosis and spermiogenesis. It has thus been postulated to be a key regulator of transcription in meiotic and post-meiotic cells. To understand the function of BRDT in regulating gene expression, we characterized its genome-wide distribution, in particular the features of the BRDT binding sites within gene units, by ChIP-Seq analysis of enriched fractions of spermatocytes and spermatids. In both cell types, BRDT binding sites were mainly located in promoters, first exon, and introns of genes that are highly transcribed during meiosis and spermiogenesis. Furthermore, in promoters, BRDT binding sites overlapped with several histone modifications and histone variants associated with active transcription, and were also enriched for consensus sequences for specific transcription factors, including MYB, RFX, ETS and ELF1 in pachytene spermatocytes, and JunD, c-Jun, CRE and RFX in round spermatids. Our analysis further revealed that BRDT-bound genes play key roles in diverse biological processes that are essential for proper spermatogenesis. Taken together, our data suggest that BRDT is involved in the recruitment of different transcription factors to distinctive chromatin regions within gene units to regulate diverse downstream target genes that function in male meiosis and spermiogenesis.

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Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter

Biochemical Journal ◽

10.1042/bj3370253 ◽

1999 ◽

Vol 337 (2) ◽

pp. 253-262 ◽

Cited By ~ 13

Author(s):

Lucia PELLIZZARI ◽

Gianluca TELL ◽

Giuseppe DAMANTE

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Dna Sequences ◽

Target Genes ◽

Dna Recognition ◽

Cell Types ◽

Full Length ◽

Paired Domain ◽

Binding Properties ◽

Evolutionarily Conserved

Pax proteins are transcription factors that play an important role in the differentiation of several cell types. These proteins bind to specific DNA sequences through the paired domain. This evolutionarily conserved element is composed of two subdomains (PAI and RED), located at the N- and C-terminals, respectively. Due to the presence of these two subdomains, Pax proteins may recognize DNA in different modes, a possibility that has not been exhaustively explored yet. The C site of the thyroglobulin promoter is bound by the thyroid-specific transcription factor Pax-8. In this study we have characterized the mode by which the Pax-8 paired domain interacts with the C site. Results allow the identification of the respective positions of the PAI and RED subdomains when the full-length protein is bound to the C site. The binding of the isolated PAI and RED subdomains to the C site and to several related mutants was also evaluated. Both subdomains interact with DNA as a monomer and display a lower binding affinity than the full-length protein. Therefore, the Pax-8 paired domain–C site interaction occurs through a co-operation between the two subdomains. The binding properties of the PAI subdomain suggest that the co-operation between PAI and RED subdomains does not merely consist of the sum of contacts established by the single subdomain: the presence of the RED subdomain is necessary for correct DNA recognition by the PAI subdomain, thus accounting for a sort of chronology of events during DNA binding. Since the RED subdomain is much more variable than the PAI subdomain among Pax proteins, these results could explain how distinct Pax proteins may select different target genes.

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Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in T-Cell Acute Lymphoblastic Leukemia,

Blood ◽

10.1182/blood.v118.21.3453.3453 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3453-3453

Author(s):

Takaomi Sanda ◽

Lee N Lawton ◽

M Inmaculada Barrasa ◽

Zi Peng Fan ◽

Yebin Ahn ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Target Genes ◽

Lymphoblastic Leukemia ◽

Regulatory Circuit ◽

Transcriptional Regulatory ◽

Cell Acute Lymphoblastic Leukemia ◽

Direct Target ◽

Regulatory Loop ◽

Oncogenic Transcription Factor

Abstract Abstract 3453 Aberrant expression of TAL1 is one of the most frequent abnormalities in T-cell acute lymphoblastic leukemia (T-ALL), yet little is known about the transcriptional network controlled by this oncogenic transcription factor, posing a major obstacle to understanding T-ALL pathogenesis. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, GATA3 and RUNX1 in T-ALL cells. We determined direct transcriptional targets of TAL1 and its regulatory partners by ChIP-seq analysis, and found that TAL1 binds to the majority of HEB- and E2A-enriched regions and that these commonly bound regions are frequently overlapping with the GATA3- and RUNX1-enriched regions. We found that TAL1 forms an interconnected auto-regulatory loop with its partners, which likely contribute to the sustained upregulation of its direct target genes. TAL1 core regulatory circuit activates genes involved in T-cell development and hematopoesis. Microarray gene expression analysis revealed that TAL1 and GATA3 predominantly act as positive regulators of the expression of their direct target genes in T-ALL. Importantly, we found the MYB oncogenic transcription factor is directly activated by the TAL1 complex and positively regulates many of the same target genes, thus forming a feed-forward positive regulatory loop that further promotes the TAL1-regulated oncogenic program. Moreover, we found that a specific subset of TAL1 target genes are oppositely regulated by TAL1 and its obligate partner proteins E2A and HEB, uncovering a leukemogenic pattern that previously emerged from studies in murine models. These findings underscore the importance of TAL1 as a critical regulator of an aberrant gene expression program in T-ALL, and indicate how these networks maintain the malignant state in thymocytes. Disclosures: No relevant conflicts of interest to declare.

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