Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B− but not in HTR23B+ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

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Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers

Blood ◽

10.1182/blood.2019003062 ◽

2020 ◽

Vol 136 (6) ◽

pp. 698-714 ◽

Cited By ~ 5

Author(s):

Alexandre Fagnan ◽

Frederik Otzen Bagger ◽

Maria-Riera Piqué-Borràs ◽

Cathy Ignacimouttou ◽

Alexis Caulier ◽

...

Keyword(s):

Transcription Factors ◽

Molecular Mechanisms ◽

Hematologic Malignancy ◽

Ectopic Expression ◽

Leukemic Cells ◽

Erythroid Progenitors ◽

Molecular Subgroup ◽

Aberrant Expression ◽

In Vivo Models ◽

Hematopoietic Stem

Abstract Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.

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Regulation of the yjjQ-bglJ Operon, Encoding LuxR-Type Transcription Factors, and the Divergent yjjP Gene by H-NS and LeuO

Journal of Bacteriology ◽

10.1128/jb.01447-07 ◽

2007 ◽

Vol 190 (3) ◽

pp. 926-935 ◽

Cited By ~ 35

Author(s):

Thomas Stratmann ◽

S. Madhusudan ◽

Karin Schnetz

Keyword(s):

Transcription Factors ◽

Virulence Factor ◽

Binding Sites ◽

Regulatory Region ◽

Gene Encoding ◽

E Coli ◽

Divergent Promoters ◽

Nucleoprotein Complex ◽

K 12 ◽

Regulatory Sites

ABSTRACT The yjjQ and bglJ genes encode LuxR-type transcription factors conserved in several enterobacterial species. YjjQ is a potential virulence factor in avian pathogenic Escherichia coli. BglJ counteracts the silencing of the bgl (β-glucoside) operon by H-NS in E. coli K-12. Here we show that yjjQ and bglJ form an operon carried by E. coli K-12, whose expression is repressed by the histone-like nucleoid structuring (H-NS) protein. The LysR-type transcription factor LeuO counteracts this repression. Furthermore, the yjjP gene, encoding a membrane protein of unknown function and located upstream in divergent orientation to the yjjQ-bglJ operon, is likewise repressed by H-NS. Mapping of the promoters as well as the H-NS and LeuO binding sites within the 555-bp intergenic region revealed that H-NS binds to the center of the AT-rich regulatory region and distal to the divergent promoters. LeuO sites map to the center and to positions distal to the yjjQ promoters, while one LeuO binding site overlaps with the divergent yjjP promoter. This latter LeuO site is required for full derepression of the yjjQ promoters. The arrangement of regulatory sites suggests that LeuO restructures the nucleoprotein complex formed by H-NS. Furthermore, the data support the conclusion that LeuO, whose expression is likewise repressed by H-NS and which is a virulence factor in Salmonella enterica, is a master regulator that among other loci, also controls the yjjQ-bglJ operon and thus indirectly the presumptive targets of YjjQ and BglJ.

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Plenary Lecture 2 Transcription factors, regulatory elements and nutrient–gene communication

Proceedings of The Nutrition Society ◽

10.1017/s0029665109991790 ◽

2009 ◽

Vol 69 (1) ◽

pp. 91-94 ◽

Cited By ~ 5

Author(s):

Robert J. Cousins ◽

Tolunay B. Aydemir ◽

Louis A. Lichten

Keyword(s):

Transcription Factors ◽

Histone Acetylation ◽

Intracellular Transport ◽

Molecular Mechanisms ◽

Gene Activation ◽

Regulatory Elements ◽

Atp Citrate Lyase ◽

Signalling Molecules ◽

Citrate Lyase ◽

Normal Metabolism

Dramatic advances have been made in the understanding of the differing molecular mechanisms used by nutrients to regulate genes that are essential for their biological roles to carry out normal metabolism. Classical studies have focused on nutrients as ligands to activate specific transcription factors. New interest has focused on histone acetylation as a process for either global or limited gene activation and is the first mechanism to be discussed. Nuclear ATP-citrate lyase generates acetyl-CoA, which has been shown to have a role in the activation of specific genes via selective histone acetylation. Transcription factor acetylation may provide a second mode of control of nutrient-responsive gene transcription. The third mechanism relates to the availability of response elements within chromatin, which as well as the location of the elements in the gene may allow or prevent transcription. A fourth mechanism involves intracellular transport of Zn ions, which can orchestrate localized enzyme inhibition–activation. This process in turn influences signalling molecules that regulate gene expression. The examples provided in the present review point to a new level of complexity in understanding nutrient–gene communication.

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Repression of Nanog Gene Transcription by Tcf3 Limits Embryonic Stem Cell Self-Renewal

Molecular and Cellular Biology ◽

10.1128/mcb.00368-06 ◽

2006 ◽

Vol 26 (20) ◽

pp. 7479-7491 ◽

Cited By ~ 203

Author(s):

Laura Pereira ◽

Fei Yi ◽

Bradley J. Merrill

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Molecular Mechanisms ◽

Inner Cell Mass ◽

Cell Mass ◽

Regulatory Region ◽

Embryonic Stem ◽

Dual Function ◽

Self Renewal ◽

Nanog Gene

ABSTRACT The dual function of stem cells requires them not only to form new stem cells through self-renewal but also to form lineage-committed cells through differentiation. Embryonic stem cells (ESC), which are derived from the blastocyst inner cell mass, retain properties of self-renewal and the potential for lineage commitment. To balance self-renewal and differentiation, ESC must carefully control the levels of several transcription factors, including Nanog, Sox2, and Oct4. While molecular mechanisms promoting transcription of these genes have been described, mechanisms preventing excessive levels in self-renewing ESC remain unknown. By examining the function of the TCF family of transcription factors in ESC, we have found that Tcf3 is necessary to limit the steady-state levels of Nanog mRNA, protein, and promoter activity in self-renewing ESC. Chromatin immunoprecipitation and promoter reporter assays showed that Tcf3 bound to a promoter regulatory region of the Nanog gene and repressed its transcriptional activity in ESC through a Groucho interaction domain-dependent process. The absence of Tcf3 caused delayed differentiation of ESC in vitro as elevated Nanog levels persisted through 5 days of embryoid body formation. These new data support a model wherein Tcf3-mediated control of Nanog levels allows stem cells to balance the creation of lineage-committed and undifferentiated cells.

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Genome-Wide Identification and Characterization of bHLH Transcription Factors Related to Anthocyanin Biosynthesis in Red Walnut (Juglans regia L.)

Frontiers in Genetics ◽

10.3389/fgene.2021.632509 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wei Zhao ◽

Yonghui Liu ◽

Lin Li ◽

Haijun Meng ◽

Ying Yang ◽

...

Keyword(s):

Transcription Factors ◽

Gene Family ◽

Developmental Stage ◽

Molecular Mechanisms ◽

Anthocyanin Biosynthesis ◽

Expression Profiles ◽

Juglans Regia ◽

Expression Patterns ◽

Regulatory Elements

Basic helix-loop-helix (bHLH) proteins are transcription factors (TFs) that have been shown to regulate anthocyanin biosynthesis in many plant species. However, the bHLH gene family in walnut (Juglans regia L.) has not yet been reported. In this study, 102 bHLH genes were identified in the walnut genome and were classified into 15 subfamilies according to sequence similarity and phylogenetic relationships. The gene structure, conserved domains, and chromosome location of the genes were analyzed by bioinformatic methods. Gene duplication analyses revealed that 42 JrbHLHs were involved in the expansion of the walnut bHLH gene family. We also characterized cis-regulatory elements of these genes and performed Gene Ontology enrichment analysis of gene functions, and examined protein-protein interactions. Four candidate genes (JrEGL1a, JrEGL1b, JrbHLHA1, and JrbHLHA2) were found to have high homology to genes encoding bHLH TFs involved in anthocyanin biosynthesis in other plants. RNA sequencing revealed tissue- and developmental stage-specific expression profiles and distinct expression patterns of JrbHLHs according to phenotype (red vs. green leaves) and developmental stage in red walnut hybrid progeny, which were confirmed by quantitative real-time PCR analysis. All four of the candidate JrbHLH proteins localized to the nucleus, consistent with a TF function. These results provide a basis for the functional characterization of bHLH genes and investigations on the molecular mechanisms of anthocyanin biosynthesis in red walnut.

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Isolation, sequence, and differential expression of a human K7 gene in simple epithelial cells.

The Journal of Cell Biology ◽

10.1083/jcb.107.4.1337 ◽

1988 ◽

Vol 107 (4) ◽

pp. 1337-1350 ◽

Cited By ~ 30

Author(s):

C Glass ◽

E Fuchs

Keyword(s):

Epithelial Cells ◽

Differential Expression ◽

Molecular Mechanisms ◽

Human Gene ◽

Cell Types ◽

Regulatory Elements ◽

Gene Encoding ◽

Keratin Gene ◽

Base Level ◽

Different Cell Types

Simple epithelial cells synthesize a different set of keratins than epidermal cells. In experiments reported in this manuscript, we show that the base level of keratin expression in simple epithelial cells is variable for different cell types, and that, in some simple epithelia, this level can be upregulated by increasing the exposure of cells to retinoids, but not glucocorticoids or estradiol. To elucidate the molecular mechanisms underlying simple epithelial keratin gene regulation, we have isolated and characterized a human gene encoding the simple epithelial keratin K7. By examining the possible regulatory elements of this gene and by investigating the behavior of this gene introduced transiently into simple epithelial cells, we have uncovered a possible basis for the differential expression of epidermal and simple epithelial keratin genes.

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Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis

Development ◽

10.1242/dev.126.19.4223 ◽

1999 ◽

Vol 126 (19) ◽

pp. 4223-4234 ◽

Cited By ~ 2

Author(s):

H. Kuo ◽

J. Chen ◽

P. Ruiz-Lozano ◽

Y. Zou ◽

M. Nemer ◽

...

Keyword(s):

Transgene Expression ◽

Molecular Mechanisms ◽

Regulatory Region ◽

Regulatory Elements ◽

Ankyrin Repeat ◽

Specific Marker ◽

Sequence Element ◽

Regulatory Pathways ◽

Repeat Protein ◽

Ankyrin Repeat Protein

Although accumulating evidence suggests that the heart develops in a segmental fashion, the molecular mechanisms that control regional specification of cardiomyocytes in the developing heart remain largely unknown. In this study, we have used the mouse cardiac-restricted ankyrin repeat protein (CARP) gene as a model system to study these mechanisms. The CARP gene encodes a nuclear co-regulator for cardiac gene expression, which lies downstream of the cardiac homeobox gene, Nkx 2.5, and is an early marker of the cardiac muscle cell lineage. We have demonstrated that the expression of the gene is developmentally down regulated and dramatically induced as part of the embryonic gene program during cardiac hypertrophy. Using a lacZ/knock-in mouse and three lines of transgenic mouse harboring various CARP promoter/lacZ reporters, we have identified distinct 5′ cis regulatory elements of the gene that can direct heart segment-specific transgene expression, such as atrial versus ventricular and left versus right. Most interestingly, a 213 base pair sequence element of the gene was found to confer conotruncal segment-specific transgene expression. Using the transgene as a conotruncal segment-specific marker, we were able to document the developmental fate of a subset of cardiomyocytes in the conotruncus during cardiogenesis. In addition, we have identified an essential GATA-4 binding site in the proximal upstream regulatory region of the gene and cooperative transcriptional regulation mediated by Nkx2.5 and GATA-4. We have shown that this cooperative regulation is dependent on binding of GATA-4 to its cognate DNA sequence in the promoter, which suggests that Nkx2.5 controls CARP expression, at least in part, through GATA-4.

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Ancestral and derived transcriptional enhancers share regulatory sequence and a pleiotropic site affecting chromatin accessibility

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004003117 ◽

2020 ◽

Vol 117 (34) ◽

pp. 20636-20644 ◽

Cited By ~ 1

Author(s):

Yaqun Xin ◽

Yann Le Poul ◽

Liucong Ling ◽

Mariam Museridze ◽

Bettina Mühling ◽

...

Keyword(s):

Molecular Mechanisms ◽

Regulatory Region ◽

Gene Expression Pattern ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Regulatory Sequence ◽

The Novel ◽

Regulatory Activity ◽

Dna Accessibility ◽

Multicellular Organisms

The diversity of forms in multicellular organisms originates largely from the spatial redeployment of developmental genes [S. B. Carroll,Cell134, 25–36 (2008)]. Several scenarios can explain the emergence ofcis-regulatory elements that govern novel aspects of a gene expression pattern [M. Rebeiz, M. Tsiantis,Curr. Opin. Genet. Dev.45, 115–123 (2017)]. One scenario, enhancer co-option, holds that a DNA sequence producing an ancestral regulatory activity also becomes the template for a new regulatory activity, sharing regulatory information. While enhancer co-option might fuel morphological diversification, it has rarely been documented [W. J. Glassford et al.,Dev. Cell34, 520–531 (2015)]. Moreover, if two regulatory activities are borne from the same sequence, their modularity, considered a defining feature of enhancers [J. Banerji, L. Olson, W. Schaffner,Cell33, 729–740 (1983)], might be affected by pleiotropy. Sequence overlap may thereby play a determinant role in enhancer function and evolution. Here, we investigated this problem with two regulatory activities of theDrosophilageneyellow, the novelspotenhancer and the ancestralwing bladeenhancer. We used precise and comprehensive quantification of each activity inDrosophilawings to systematically map their sequences along the locus. We show that thespotenhancer has co-opted the sequences of thewing bladeenhancer. We also identified a pleiotropic site necessary for DNA accessibility of a shared regulatory region. While the evolutionary steps leading to the derived activity are still unknown, such pleiotropy suggests that enhancer accessibility could be one of the molecular mechanisms seeding evolutionary co-option.

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TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.048 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii11-ii11

Author(s):

Daisuke Kawauchi ◽

Kristian Pajtler ◽

Yiju Wei ◽

Konstantin Okonechnikov ◽

Patricia Silva ◽

...

Keyword(s):

Transcription Factors ◽

Binding Site ◽

Nuclear Localization ◽

Molecular Mechanisms ◽

Regulatory Elements ◽

Molecular Characteristics ◽

Independent Manner ◽

Chromatin Immunoprecipitation Sequencing ◽

Localization Signal ◽

Oncogenic Driver

Abstract YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

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Genetic and Biochemical Analysis of cis Regulatory Elements within the Keratinocyte Enhancer Region of the Human Papillomavirus Type 31 Upstream Regulatory Region during Different Stages of the Viral Life Cycle

Journal of Virology ◽

10.1128/jvi.78.2.612-629.2004 ◽

2004 ◽

Vol 78 (2) ◽

pp. 612-629 ◽

Cited By ~ 18

Author(s):

Ellora Sen ◽

Samina Alam ◽

Craig Meyers

Keyword(s):

Transcription Factors ◽

Human Papillomavirus ◽

Life Cycle ◽

Mutational Analysis ◽

Regulatory Region ◽

Regulatory Elements ◽

Viral Life Cycle ◽

Keratinocyte Differentiation ◽

Viral Gene ◽

Upstream Regulatory Region

ABSTRACT Using linker scanning mutational analysis, we recently identified potential cis regulatory elements contained within the 5′ upstream regulatory region (URR) domain and auxiliary enhancer (AE) region of the human papillomavirus type 31 (HPV31) URR involved in the regulation of E6/E7 promoter activity at different stages of the viral life cycle. For the present study, we extended the linker scanning mutational analysis to identify potential cis elements located in the keratinocyte enhancer (KE) region (nucleotides 7511 to 7762) of the HPV31 URR and to characterize cellular factors that bind to these elements under conditions representing different stages of the viral life cycle. The linker scanning mutational analysis identified viral cis elements located in the KE region that regulate transcription in the presence and absence of any viral gene products or viral DNA replication and determine the role of host tissue differentiation on viral transcriptional regulation. Using electrophoretic mobility shift assays, we illustrated defined reorganization in the composition of cellular transcription factors binding to the same cis regulatory elements at different stages of the HPV differentiation-dependent life cycle. Our studies provide an extensive map of functional elements in the KE region of the HPV31 URR, identify cis regulatory elements that exhibit significant transcription regulatory potential, and illustrate changes in specific protein-DNA interactions at different stages of the viral life cycle. The variable recruitment of transcription factors to the same cis element under different cellular conditions may represent a mechanism underlying the tight link between keratinocyte differentiation and E6/E7 expression.

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