Transcription Control of Liver Development

During liver organogenesis, cellular transcriptional profiles are constantly reshaped by the action of hepatic transcriptional regulators, including FoxA1-3, GATA4/6, HNF1α/β, HNF4α, HNF6, OC-2, C/EBPα/β, Hex, and Prox1. These factors are crucial for the activation of hepatic genes that, in the context of compact chromatin, cannot access their targets. The initial opening of highly condensed chromatin is executed by a special class of transcription factors known as pioneer factors. They bind and destabilize highly condensed chromatin and facilitate access to other “non-pioneer” factors. The association of target genes with pioneer and non-pioneer transcription factors takes place long before gene activation. In this way, the underlying gene regulatory regions are marked for future activation. The process is called “bookmarking”, which confers transcriptional competence on target genes. Developmental bookmarking is accompanied by a dynamic maturation process, which prepares the genomic loci for stable and efficient transcription. Stable hepatic expression profiles are maintained during development and adulthood by the constant availability of the main regulators. This is achieved by a self-sustaining regulatory network that is established by complex cross-regulatory interactions between the major regulators. This network gradually grows during liver development and provides an epigenetic memory mechanism for safeguarding the optimal expression of the regulators.

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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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HNF-1α and endodermal transcription factors cooperatively activate Fabpl: MODY3 mutations abrogate cooperativity

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00074.2003 ◽

2003 ◽

Vol 285 (1) ◽

pp. G62-G72 ◽

Cited By ~ 31

Author(s):

Joyce K. Divine ◽

Sean P. McCaul ◽

Theodore C. Simon

Keyword(s):

Transcription Factors ◽

Gene Activation ◽

The Other ◽

Wild Type ◽

Critical Determinant ◽

Fatty Acid Binding ◽

Hepatic Expression ◽

Synergistic Activation ◽

Five Factors

Hepatocyte nuclear factor (HNF)-1α plays a central role in intestinal and hepatic gene regulation and is required for hepatic expression of the liver fatty acid binding protein gene ( Fabpl). An Fabpl transgene was directly activated through cognate sites by HNF-1α and HNF-1β, as well as five other endodermal factors: CDX-1, C/EBPβ, GATA-4, FoxA2, and HNF-4α. HNF-1α activated the Fabpl transgene by as much as 60-fold greater in the presence of the other five endodermal factors than in their absence, accounting for up to one-half the total transgene activation by the group of six factors. This degree of synergistic interaction suggests that multifactor cooperativity is a critical determinant of endodermal gene activation by HNF-1α. Mutations in HNF-1α that result in maturity onset diabetes of the young (MODY3) provide evidence for the in vivo significance of these synergistic interactions. An R131Q HNF-1α MODY3 mutant exhibits complete loss of synergistic activation in concert with the other endodermal transcription factors despite wild-type transactivation ability in their absence. Furthermore, whereas wild-type HNF-1α exhibited pairwise cooperative synergy with each of the other five factors, the R131Q mutant could synergize only with GATA-4 and C/EBPβ. Selective loss of synergy with other endodermal transcription factors accompanied by retention of native transactivation ability in an HNF-1α MODY mutant suggests in vivo significance for cooperative synergy.

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Genes Involved in the Transcriptional Regulation of Pluripotency Are Expressed in Malignant Tumors of the Uterine Cervix and Can Induce Tumorigenic Capacity in a Nontumorigenic Cell Line

Stem Cells International ◽

10.1155/2019/7683817 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Graciela Ruiz ◽

Heriberto A. Valencia-González ◽

Delia Pérez-Montiel ◽

Felipe Muñoz ◽

Rodolfo Ocadiz-Delgado ◽

...

Keyword(s):

Cervical Cancer ◽

Stem Cell ◽

Transcription Factors ◽

Cancer Stem Cell ◽

Cell Line ◽

Target Genes ◽

Malignant Tumors ◽

Expression Profiles ◽

Ectopic Expression ◽

Normal Tissues

Transcription factors OCT4, SOX2, KLF4, C-MYC, and NANOG (OSKM-N) regulate pluripotency and stemness, and their ectopic expression reprograms human and murine fibroblasts that constitute the key of regenerative medicine. To determine their contribution to cell transformation, we analyzed the gene expression profiles of these transcription factors in cervical cancer samples and found that they are preferentially expressed in the tumor component. Also, cancer stem cell-enriched cultures grown as sphere cultures showed overexpression of OSKM-N genes. Importantly, we observed that lentiviral-mediated transduction of these factors confers, to a nontumorigenic immortalized human cell line, properties of cancer stem cells as the ability to form tumors in a mouse model. When we performed a meta-analysis using microarray data from cervical cancer biopsies and normal tissues, we found that the expression of OSKM-N and some target genes allowed separating tumor and normal tissues between samples, which enhanced the importance of OSKM-N in the tumorigenesis. Finally, we analyzed and compared both transcript and protein expression profiles of these factors within a cohort of patients with cervical cancer. To our knowledge, this is the first time that the expression of OSKM-N is described to induce one of the main characteristics of the cancer stem cell, the tumorigenicity. And, more importantly, its exogenous expression in a nontumorigenic cell line is sufficient to induce a tumorigenic phenotype; furthermore, the differential expression of this transcription factor distinguishes tumor tissue and normal tissue in cervical samples.

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Analysis of temporal changes in the expression of estrogen-regulated genes in the uterus

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0300347 ◽

2003 ◽

Vol 30 (3) ◽

pp. 347-358 ◽

Cited By ~ 59

Author(s):

H Watanabe ◽

A Suzuki ◽

M Kobayashi ◽

E Takahashi ◽

M Itamoto ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Expression Profiles ◽

Gene Activation ◽

Gene Expression Profiles ◽

Ovariectomized Mice ◽

Two Phases ◽

Er Alpha ◽

Inducible Genes

In order to understand early events caused by estrogen in vivo, temporal uterine gene expression profiles at early stages were examined using DNA microarray analysis. Ovariectomized mice were exposed to 17beta-estradiol and the temporal mRNA expression changes of ten thousand various genes were analyzed. Clustering analysis revealed that there are at least two phases of gene activation during the period up to six hours. One involved immediate-early genes, which included certain transcription factors and growth factors as well as oncogenes. The other involved early-late genes, which included genes related to RNA and protein synthesis. In clusters of down-regulated genes, transcription factors, proteases, apoptosis and cell cycle genes were found. These hormone-inducible genes were not induced in estrogen receptor (ER) alpha knockout mice. Although expression of ERbeta is known in the uterus, these findings indicate the importance of ERalpha in the changes in gene expression in the uterus.

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Identification of hydatidosis-related modules and key regulatory genes

PeerJ ◽

10.7717/peerj.9280 ◽

2020 ◽

Vol 8 ◽

pp. e9280

Author(s):

Jijun Song ◽

Mingxin Song

Keyword(s):

Transcription Factors ◽

Signaling Pathway ◽

Target Genes ◽

Expression Profiles ◽

Differential Expression Analysis ◽

Interaction Network ◽

Enrichment Analysis ◽

Bmp Signaling ◽

Differentially Expressed ◽

Regulatory Effects

Background Echinococcosis caused by larval of Echinococcus is prevalent all over the world. Although clinical experience showed that the presence of tapeworms could not be found in liver lesions, the repeated infection and aggravation of lesions still occur in the host. Here, this study constructed a multifactor-driven disease-related dysfunction network to explore the potential molecular pathogenesis mechanism in different hosts after E.multilocularis infection. Method First, iTRAQ sequencing was performed on human liver infected with E.multilocularis. Second, obtained microRNAs(miRNAs) expression profiles of humans and canine infected with Echinococcus from the GEO database. In addition, we also performed differential expression analysis, protein interaction network analysis, enrichment analysis, and crosstalk analysis to obtain genes and modules related to E.multilocularis infection. Pivot analysis is used to calculate the potential regulatory effects of multiple factors on the module and identify related non-coding RNAs(ncRNAs) and transcription factors(TFs). Finally, we screened the target genes of miRNAs of Echinococcus to further explore its infection mechanism. Results A total of 267 differentially expressed proteins from humans and 3,635 differentially expressed genes from canine were obtained. They participated in 16 human-related dysfunction modules and five canine-related dysfunction modules, respectively. Both human and canine dysfunction modules are significantly involved in BMP signaling pathway and TGF-beta signaling pathway. In addition, pivot analysis found that 1,129 ncRNAs and 110 TFs significantly regulated human dysfunction modules, 158 ncRNAs and nine TFs significantly regulated canine dysfunction modules. Surprisingly, the Echinococcus miR-184 plays a role in the pathogenicity regulation by targeting nine TFs and one ncRNA in humans. Similarly, miR-184 can also cause physiological dysfunction by regulating two transcription factors in canine. Conclusion The results show that the miRNA-184 of Echinococcus can regulate the pathogenic process through various biological functions and pathways. The results laid a solid theoretical foundation for biologists to further explore the pathogenic mechanism of Echinococcosis.

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Characterization of the microRNA Expression Profiles in the Goat Kid Liver

Frontiers in Genetics ◽

10.3389/fgene.2021.794157 ◽

2022 ◽

Vol 12 ◽

Author(s):

Xiaodong Zhao ◽

Zhibin Ji ◽

Rong Xuan ◽

Aili Wang ◽

Qing Li ◽

...

Keyword(s):

Differential Expression ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Target Genes ◽

Expression Profiles ◽

Expression Patterns ◽

Metabolic Process ◽

Liver Development ◽

Hormone Synthesis ◽

Liver Tissues

The liver is the largest digestive gland in goats with an important role in early metabolic function development. MicroRNAs (miRNA) are crucial for regulating the development and metabolism in the goat liver. In the study, we sequenced the miRNAs in the liver tissues of the goat kid to further research their regulation roles in early liver development. The liver tissues were procured at 5-time points from the Laiwu black goats of 1 day (D1), 2 weeks (W2), 4 weeks (W4), 8 weeks (W8), and 12 weeks (W12) after birth, respectively with five goats per time point, for a total of 25 goats. Our study identified 214 differential expression miRNAs, and the expression patterns of 15 randomly selected miRNAs were examined among all five age groups. The Gene ontology annotation results showed that differential expression miRNA (DE miRNA) target genes were significantly enriched in the fatty acid synthase activity, toxin metabolic process, cell surface, and antibiotic metabolic process. The KEGG analysis result was significantly enriched in steroid hormone synthesis and retinol metabolism pathways. Further miRNA-mRNA regulation network analysis reveals 9 differently expressed miRNA with important regulation roles. Overall, the DE miRNAs were mainly involved in liver development, lipid metabolism, toxin related metabolism-related biological process, and pathways. Our results provide new information about the molecular mechanisms and pathways in the goat kid liver development.

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FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors

Blood ◽

10.1182/blood-2019-126201 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1228-1228

Author(s):

Yanan Li ◽

Riddhi M Patel ◽

Emily Casey ◽

Jeffrey A. Magee

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Target Gene ◽

Target Genes ◽

Conflicts Of Interest ◽

Gene Activation ◽

Chromatin Accessibility ◽

Luciferase Reporter ◽

Enhancer Activity ◽

Target Gene Expression

The FLT3 Internal Tandem Duplication (FLT3ITD) is common somatic mutation in acute myeloid leukemia (AML). We have previously shown that FLT3ITD fails to induce changes in HSC self-renewal, myelopoiesis and leukemogenesis during fetal stages of life. FLT3ITD signal transduction pathways are hyperactivated in fetal progenitors, but FLT3ITD target genes are not. This suggests that postnatal-specific transcription factors may be required to help induce FLT3ITD target gene expression. Alternatively, repressive histone modifications may impose a barrier to FLT3ITD target gene activation in fetal HPCs that is relaxed during postnatal development. To resolve these possibilities, we used ATAC-seq, as well as H3K4me1, H3K27ac and H3K27me3 ChIP-seq, to identify cis-elements that putatively control FLT3ITD target gene expression in fetal and adult hematopoietic progenitor cells (HPCs). We identified many enhancer elements (ATAC-seq peaks with H3K4me1 and H3K27ac) that exhibited increased chromatin accessibility and activity in FLT3ITD adult HPCs relative to wild type adult HPCs. These elements were enriched near FLT3ITD target genes. HOMER analysis showed enrichment for STAT5, ETS, RUNX1 and IRF binding motifs within the FLT3ITD target enhancers, but motifs for temporally dynamic transcription factors were not identified. We cloned a subset of the enhancers and confirmed that they could synergize with their promoter to activate a luciferase reporter. For representative enhancers, STAT5 binding sites were required to activate the enhancer - as anticipated - and RUNX1 repressed enhancer activity. We tested whether accessibility or priming changed between fetal and adult stages of HPC development. FLT3ITD-dependent changes in chromatin accessibility were not observed in fetal HPCs, though the enhancers were primed early in development as evidenced by the presence of H3K4me1. Repressive H3K27me3 were not present at FLT3ITD target enhancers in either or adult HPCs. The data show that FLT3ITD target enhancers are demarcated early in hematopoietic development, long before they become responsive to FLT3ITD signaling. Repressive marks do not appear to create an epigenetic barrier to enhancer activation in the fetal stage. Instead, age-specific transcription factors are likely required to pioneer enhancer elements so that they can respond to STAT5 and other FLT3ITD effectors. Disclosures No relevant conflicts of interest to declare.

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Expression Profiling Identifies TWIST2 Target Genes in Setleis Syndrome Patient Fibroblast and Lymphoblast Cells

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18041997 ◽

2021 ◽

Vol 18 (4) ◽

pp. 1997

Author(s):

Noe E. Crespo ◽

Alexandra Torres-Bracero ◽

Jessicca Y. Renta ◽

Robert J. Desnick ◽

Carmen L. Cadilla

Keyword(s):

Expression Profiling ◽

Target Genes ◽

Expression Profiles ◽

Gene Activation ◽

Gene Expression Profiles ◽

Autosomal Recessive Disorder ◽

Cell Types ◽

Skin Lesions ◽

Altered Expression ◽

Facial Development

Background: Setleis syndrome (SS) is a focal facial dermal dysplasia presenting with bilateral temporal skin lesions, eyelash abnormalities and absent meibomian glands. SS is a rare autosomal recessive disorder caused by mutations in the TWIST2 gene, which codes for a transcription factor of the bHLH family known to be involved in skin and facial development. Methods: We obtained gene expression profiles by microarray analyses from control and SS patient primary skin fibroblast and lymphoblastoid cell lines. Results: Out of 983 differentially regulated genes in fibroblasts (fold change ≥ 2.0), 479 were down-regulated and 509 were up-regulated, while in lymphoblasts, 1248 genes were down-regulated and 73 up-regulated. RT-PCR reactions confirmed altered expression of selected genes. Conclusions: TWIST2 is described as a repressor, but expression profiling suggests an important role in gene activation as well, as evidenced by the number of genes that are down-regulated, with a much higher proportion of down-regulated genes found in lymphoblastoid cells from an SS patient. As expected, both types of cell types showed dysregulation of cytokine genes. These results identify potential TWIST2 target genes in two important cell types relevant to rare disorders caused by mutations in this bHLH gene.

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Identification of MicroRNAs and Their Targets Involved in Paeonia rockii Petal Variegation Using High-throughput Sequencing

Journal of the American Society for Horticultural Science ◽

10.21273/jashs04395-18 ◽

2019 ◽

Vol 144 (2) ◽

pp. 118-129 ◽

Cited By ~ 1

Author(s):

Qianqian Shi ◽

Xiaoxiao Zhang ◽

Xiang Li ◽

Lijuan Zhai ◽

Xiaoning Luo ◽

...

Keyword(s):

Transcription Factors ◽

Posttranscriptional Regulation ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Target Genes ◽

Expression Profiles ◽

Tree Peony ◽

Flower Opening ◽

Paeonia Rockii ◽

Flower Pigmentation

Tree peony (Paeonia sp.) is a popular traditional ornamental plant in China. Among the nine wild species, Paeonia rockii displays wide-ranging, deep purple variegation at the base of the petals, whereas Paeonia ostii exhibits purely white petals. Overall, the posttranscriptional regulation involved in tree peony flower opening and pigmentation remains unclear. To identify potential microRNAs (miRNAs) involved in flower variegation, six small RNA libraries of P. ostii and P. rockii petals at three different opening stages were constructed and sequenced. Using Illumina-based sequencing, 22 conserved miRNAs and 27 novel miRNAs were identified in P. rockii and P. ostii petals. Seventeen miRNAs were differentially expressed during flower development, and several putative target genes of these miRNAs belonged to transcription factor families, such as Myb domain (MYB), and basic helix-loop-helix (bHLH) transcription factors. Furthermore, an integrative analysis of the expression profiles of miRNAs and their corresponding target genes revealed that variegation formation might be regulated by miR159c, miR168, miR396a, and novel_miR_05, which target the MYB transcription factors, chalcone synthase (CHS), and ABC transporter. Our preliminary study is the first report of miRNAs involved in Paeonia flower pigmentation. It provides insight regarding the molecular mechanisms underlying the regulation of flower pigmentation in tree peony.

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