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PubMed1997

Epidermal differentiation and squamous metaplasia: from stem cell to cell death.

Epidermal differentiation is a multi-step process defined by a cascade of interrelated changes in the expression of growth-regulatory and differentiation-specific genes (Fig. 1). Irreversible growth arrest is an early event in epidermal differentiation which occurs when cells transit from the basal to the innermost suprabasal layer of the skin and begin to express squamous-specific genes. In culture, interferon gamma, phorbol esters, confluence and growth in suspension are effective signals to induce irreversible growth arrest and differentiation. The induction of differentiation-specific genes occurs either concomitantly with or following growth arrest and is believed to be linked to the molecular events that control irreversible growth arrest. Such a link has been demonstrated in other cell systems undergoing terminal differentiation, such as myogenesis and adipogenesis. Genes encoding proteins involved in the formation of the cross-linked envelope are one set of squamous-specific genes which are induced in the suprabasal layers and include transglutaminase I and III, involucrin, loricrin and cornifins/small proline-rich proteins. Squamous-specific genes exhibit not only different patterns of tissue-specific expression but are also induced at different stages during differentiation, suggesting that transcription of individual genes is regulated by distinct mechanisms. The latter is supported by the identification of different sets of regulatory elements controlling the transcription of these genes. The importance of understanding both the mechanisms that regulate growth arrest and the differentiation program is emphasized by the association found between specific skin diseases and genetic alterations in growth-regulatory genes as well as differentiation markers. In addition, studies into those mechanisms will provide insight into the control of squamous metaplasia and the development of squamous cell carcinomas.

Amino Acid Sequence↗

PubMed2001

Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8.

Two ovine BAC clones and a connecting long-range PCR product, jointly spanning approximately 250 kb and representing most of the MULGE5-OY3 marker interval known to contain the clpg locus, were completely sequenced. The resulting genomic sequence was aligned with its human ortholog and extensively annotated. Six transcripts, four of which were novel, were predicted to originate from within the analyzed region and their existence confirmed experimentally: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. RT-PCR experiments performed on a range of tissues sampled from an 8-wk-old animal demonstrated the preferential expression of all six transcripts in skeletal muscle, which suggests that they are under control of common regulatory elements. The six transcripts were also shown to be subject to parental imprinting: DLK1, DAT, and PEG11 were shown to be paternally expressed and GTL2, antiPEG11, and MEG8 to be maternally expressed.

Animals↗

PubMed1996

Role for sterol regulatory element binding protein in the regulation of farnesyl diphosphate synthase and in the control of cellular levels of cholesterol and triglyceride: evidence from sterol regulation-defective cells.

In order to define the factors involved in the regulation of farnesyl diphosphate (FPP) synthase, we used sterol regulation-defective (SRD) cell lines that constitutively express either high (SRD-2) or low (SRD-6) levels of transcriptionally active sterol regulatory element binding protein (SREBP). FPP synthase mRNA levels were high in SRD-2 cells and low in SRD-6 cells and were unaffected by the addition or removal of sterols from the media. In contrast, the mRNA levels in parental CHO-7 cells were regulated by sterols. SRD-2, SRD-6, and CHO-7 cells were also transiently transfected with plasmids containing FPP synthase promoter-reporter genes. Reporter gene activity was significantly higher in SRD-2 cells than in either SRD-6 or CHO-7 cells, consistent with a higher rate of transcription of the reporter gene in SRD-2 cells. The high expression of the reporter gene in SRD-2 cells was not observed when the FPP synthase promoter contained a three base pair mutation within an SREBP binding site, termed sterol regulatory element-3 (SRE-3). These observations are consistent with the hypothesis that high levels of transcription of the FPP synthase gene are dependent on the availability of transcriptionally active SREBP. We also demonstrate that the incorporation of radioactive acetate into both cholesterol and fatty acids was enhanced in SRD-2 cells as compared to CHO-7 or SRD-6 cells. Finally, we demonstrate that the concentrations of cholesterol, cholesteryl ester, and triglyceride were all significantly elevated in SRD-2 cells. We conclude that SREBP is involved not only in the regulation of FPP synthase and cholesterogenesis but also in fatty acid and triglyceride synthesis.

Acetates↗

PubMed1984

Attenuation in SV40 as a mechanism of transcription-termination by RNA polymerase B.

Nuclei which were isolated from SV40 infected cells with a hypotonic detergent-free buffer were used to establish in vitro conditions which lead to transcription-termination at the attenuation site of SV40. This system allowed us to identify regulatory elements involved in transcription-termination by RNA polymerase B transcribing SV40. Transcription-termination at the attenuation site was found to be ionic strength dependent. Efficient termination occurred at low (100 mM NaCl) but not at high (100 mM (NH4)2 SO4 or 300 mM NaCl) ionic strength. When nuclei were prewashed with 300 mM NaCl, the efficiency of transcription-termination was low even when transcription was carried out at low ionic strength (100 mM NaCl). Efficient transcription-termination in the high salt prewashed nuclei was reconstituted by complementation with a high salt (300 mM NaCl) soluble factor extracted from nuclei of uninfected cells. In addition, the efficiency of transcription-termination was significantly reduced when ITP replaced GTP in the transcription reaction mixture. Our data indicate that a nuclear factor and RNA secondary structure are essential regulatory elements involved in transcription-termination by RNA polymerase B.

Animals↗

PubMedDate not supplied

YY1 transcription factor is not responsible for the negative regulation of hamster Muc1 transcription.

Muc1 is the cell surface glycoprotein abundantly expressed in cancer cells and has been shown to be involved in tumor metastasis and promotion. Recently, we identified a 37 bp segment on the hamster Muc1 promoter with the ability to suppress Muc1 transcription. This 37 bp putative negative regulatory element (NRE) binds to a transcriptional regulator Yin Yang 1 (YY1). In the present study, we examined whether binding of YY1 is responsible for the negative regulatory effect by the 37 bp segment using a hamster pancreatic cancer cell line, HP-1 cells, transfected with various expression plasmid constructs. Our results showed that: (1) overexpression of YY1 up-regulated the transcriptional activity of the full-length hamster Muc1 promoter in a dose-dependent manner; (2) the mutation of the YY1 binding site did not affect either the basal transcriptional activity or the increased transcriptional activity by YY1; and (3) even the deletion of the 37 bp NRE segment could not abrogate the increased transcriptional activity by YY1. We conclude that the NRE acts in a YY1-independent manner and that YY1 instead enhances Muc1 transcriptional activity. Further study of the precise mechanism by which YY1 augments Muc1 gene expression should be worthwhile.

Animals↗

PubMed1998

Differentiation of a catecholaminergic CNS cell line modifies tyrosine hydroxylase transcriptional regulation.

Recently, a tyrosine hydroxylase (TH)-expressing CNS-derived cell line, CAD, was obtained that is capable of undergoing reversible morphological differentiation. The isolation of the CAD line allowed us to ask whether different DNA regulatory elements direct TH transcription when cells are growing and undifferentiated versus postmitotic and differentiated. To this end, we compared expression of a transiently transfected bacterial chloramphenicol acetyltransferase reporter gene under the transcriptional control of TH 5' flanking DNA in CAD cells grown in the presence and absence of serum. Mutational analysis indicates that CAD cells differently regulate TH transcription depending on their state of differentiation. In both states, the cyclic AMP response element and AP1 site each activate transcription. However, in undifferentiated cells, the dyad/E-box element represses expression by approximately 2.7-fold, whereas it modestly activates transcription in differentiated cells. The role of the dyad/ E-box as a repressor correlates well with the two- to threefold lower amount of endogenous TH protein present in the undifferentiated CAD cells. This study demonstrates the differential use of TH DNA regulatory elements in proliferating, undifferentiated and nonproliferating, differentiated immortalized neuronal cells.

Animals↗

PubMed1999

An upstream repressor element that contributes to hepatocyte-specific expression of the rat serum amyloid A1 gene.

Serum amyloid A (SAA) is a major acute-phase protein whose expression can be dramatically induced in response to tissue damage, infection, and inflammation. Its expression is highly tissue-specific, restricted almost exclusively to liver hepatocytes. We have shown that a 320-bp fragment of the rat SAA1 promoter could confer liver-cell-specific expression on a reporter gene when transfected into cultured cells. Here we report the identification of a 29-bp regulatory element that possesses inhibitory activities on SAA1 promoter in HeLa cells but has no such effects in liver cells. Moreover, this regulatory element has properties of a transcriptional repressor; in that, it can function with a heterologous promoter and is independent of orientation and distance from the transcription initiation site. Protein binding studies showed that this regulatory element can form specific protein-DNA complexes with nuclear proteins from several nonliver cell lines (HeLa, 10T(1/2), and C2) and placenta. However, the same DNA-protein complex was not detected in extracts from liver or liver-derived cell lines (HepG2 and Hep3B). Taken together, our results demonstrate the presence of a DNA-binding protein, termed tissue-specific repressor, found only in nonhepatocytes which may function to repress SAA1 gene expression by interacting with a repressor element. Thus, liver-specific expression of the SAA1 gene is apparently regulated by both positive and negative regulatory elements and their interacting transcription factors to ensure that it is expressed only in suitable cell types.

Animals↗

PubMed2005

Cloning and molecular analysis of the regulatory factor HlMyb1 in hop (Humulus lupulus L.) and the potential of hop to produce bioactive prenylated flavonoids.

The concentrations of prenylated chalcones and bitter acids were analyzed in Czech hop varieties. The highest levels of (xanthohumol + desmethylxanthohumol) (0.97%, m/m) and of total bitter acids (17.19%, m/m) were observed for cv. Agnus. The concentration ratios of bitter acids to prenylated chalcones varied depending on the genotype, thereby suggesting genetic determination by different set(s) of structural and regulatory genes. Promoter elements of the chs_H1 gene encoding a "true"chalcone synthase, a candidate gene to co-determine the biosynthesis of prenylated chalcones, were analyzed, and several boxes for cis-regulatory elements including Myb transcription factors were discovered. A cDNA library was established from glandular tissue-enriched cones of cv. Osvald's clone 72 and used to screen for Myb regulatory elements. The cDNA of the first Myb regulatory factor from hop, called HlMyb1, was cloned and analyzed. The HlMyb1 open reading frame encodes 272 amino acids (29.8 kDa), and the protein showed highest homology to the light-regulated factor AtMyb68 from Arabidopsis thaliana within the Myb domain, whereas there was no significant homology with known MYB proteins outside this domain. Unlike AtMyb68, which is expressed in mature leaves, HlMyb1 is strongly expressed in hop inflorescences and could participate in the regulation of developmental processes involved in the production of hop cones and bioactive secondary metabolites.

Acyltransferases↗

PubMed2005

Strongylocentrotus purpuratus transcription factor GATA-E binds to and represses transcription at an Otx-Goosecoid cis-regulatory element within the aboral ectoderm-specific spec2a enhancer.

During Strongylocentrotus purpuratus embryogenesis, aboral ectoderm-specific expression of spec2a relies on an upstream enhancer that confers its spatial specificity largely through repression. The purpose of this study was to determine how spec2a expression is repressed in endoderm and oral ectoderm territories. A 78-base pair DNA sequence within the enhancer contains five tightly spaced cis-regulatory elements including proximal (TAATCT) and distal (TAATCC) elements that bind to both SpOtx, a broadly distributed transcriptional activator, and SpGoosecoid (SpGsc), an oral ectoderm-restricted transcriptional repressor. We show here that these two seemingly redundant Otx/Gsc elements have distinct functions. The proximal element bound to SpGATA-E, an endomesoderm-specific transcription factor. Treatment with SpGATA-E and SpGsc morpholino antisense oligonucleotides (MASOs) resulted in enhanced transcriptional activity from the proximal element, suggesting that both factors functioned as repressors at this site. SpGATA-E MASO-treated embryos failed to express ectoderm markers, indicating a role for SpGATA-E in ectoderm differentiation. The spec2a proximal element was distinct from the corresponding element in the related spec1 enhancer, and swaps between spec1 and spec2a cis-regulatory elements indicated, that for optimal repression, the proximal element had to interact with a nearby CCAAT-binding factor element. Our results show that the recently evolved proximal element contributes to the repression of spec2a in endomesoderm and oral ectoderm territories.

Amino Acid Sequence↗

PubMed2000

The I kappa B/NF-kappa B system: a key determinant of mucosalinflammation and protection.

The ubiquitous transcription factor NF-kappa B is a central regulator of the transcriptional activation of a number of genes involved in cell adhesion, immune and proinflammatory responses, apoptosis, differentiation, and growth. Induction of these genes in intestinal epithelial cells (IECs) by activated NF-kappa B profoundly influences mucosal inflammation and repair. NF-kappa B activation requires the removal of I kappa B from NF-kappa B by inducible proteolysis, which liberates this transcription factor for migration to the nucleus, where it binds to kappa B-regulatory elements and induces transcription. I kappa B alpha degradation is incomplete and delayed in IECs, resulting in buffered responses to luminal stimuli. The stimulatory environment partially determines whether the effect of NF-kappa B is protective or deleterious for the host. kappa B-dependent proinflammatory gene expression, particularly chemokines, major histocompatibility complex class II antigens, and adhesion molecules may be extremely important in early protective responses to mucosal pathogens but, when dysregulated, could lead to the development of chronic inflammation, as seen in inflammatory bowel diseases. The key role of NF-kappa B in regulating expression of a number of proinflammatory genes makes this protein an attractive target for selective therapeutic intervention.

Animals↗

PubMed2023

H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements in embryonic stem cells.

BACKGROUND: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood. RESULTS: We perform genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and find evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 results in reduced chromatin accessibility and transcription factor (TF) binding at promoters of expressed genes in ESCs. Likewise, enrichment of the transcriptional coactivator p300 and downstream histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the acetyl lysine reader BRD4. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TF motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate. CONCLUSIONS: H3.3 facilitates DNA accessibility, transcription factor binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it does promote de novo transcription factor binding which may contribute to the dysregulation of cellular differentiation in the absence of H3.3.

Animals↗

PubMed1999

Redox-dependent regulation of interleukin-8 by tumor necrosis factor-alpha in lung epithelial cells.

Increasing evidence supports a major role for interleukin-8 (IL-8), a potent neutrophil chemoattractant, in the chronic progression of inflammatory lung diseases. The present studies were designed to characterize the molecular events involved in IL-8 induction in pulmonary epithelial cells in response to tumor necrosis factor-alpha (TNF-alpha). IL-8 induction by TNF-alpha was redox sensitive, as indicated by electron spin resonance analysis and inhibition with membrane permeable hydroxyl scavengers. Furthermore using cell transfection and mobility shift assays, it was found that transcriptional activation of the IL-8 gene required TNF-alpha-induced activation and binding of nuclear factor-kappaB (NF-kappaB)- and NF-IL-6, nuclear transcription factors to regulatory elements in the IL-8 promoter. Activation of the IL-8 promoter by these transcription factors was also redox-sensitive. This response was mediated through the TNF-R1 receptor (p55), and not the TNF-R2 (p75) receptor, although both receptors can be found on pulmonary epithelial cells. Taken together these studies indicate that TNF-alpha-induced redox changes in lung epithelial cells are responsible for the transcriptional activation of IL-8 and that coordinate activation of NF-kappaB and NF-IL-6 mediate the response.

Antigens, CD↗

PubMed1999

Postmenopausal hormone replacement therapy and the vascular wall: mechanisms of 17 beta-estradiol's effects on vascular biology.

17 beta-estradiol (E2) protects against atherosclerosis independent of changes in plasma lipoproteins in a variety of animal models, which is explained by direct effects of E2 on the vascular wall. E2 improves vasomotion by modulation of vasoconstrictor and vasodilator systems through endothelium-dependent and endothelium-independent mechanisms. E2 affects the remodeling of the vascular wall by inhibiting smooth muscle cell proliferation and accelerating reendothelialization of injured blood vessels. E2 modulates the vascular inflammatory response by inhibiting cytokine production, cytokine-induced expression of cell adhesion molecules and platelet aggregation/adhesion. This review focuses on the cellular and molecular mechanisms underlying these vasculoprotective actions of E2. E2 can act through nongenomic stimulation of membrane/intracellular mediators and/or the classical genomic pathway of steroid actions, which is dependent on transcription and protein synthesis. The existence of at least two nuclear estrogen receptor (ER) subtypes alpha and beta and a putative membrane ER present the potential of tissue-specific as well as biologically different E2 actions. Nuclear ERs act as ligand-activated transcription factors and can affect gene regulation by interaction with the classical estrogen response element or other nonreceptor transcription factors. The molecular basis of genomic E2 actions by identifying transcription factors and regulatory elements involved in the induction and inhibition of E2 regulated gene expression is only at the beginning of being understood. The impact of E2-mediated increased NO availability on the hemodynamic and antiatherosclerotic actions of E2 is still a debate of controversy.

Cytokines↗

PubMed2000

COUP-TF plays a dual role in the regulation of the ovalbumin gene.

The ovalbumin (Ov) gene contains a number of regulatory elements that control its transcriptional activity and restrict expression to avian oviduct. One major regulatory region, the steroid-dependent regulatory element (SDRE), is required for induction by estrogen and corticosterone. Another region, the negative regulatory element (NRE), downstream of the SDRE, acts primarily to repress gene expression. In addition, experiments within indicate that the binding site for the COUP transcription factor (COUP-TF) is also required for Ov gene transcription. To examine the interactions involving the SDRE, the NRE, and the COUP binding sites on Ov gene transcription, mutations in these regions were made and transfected into primary oviduct cell cultures. These experiments show that without the NRE, the SDRE is sufficient for induction by estrogen and corticosterone, irrespective of the COUP site. However, with the NRE intact, the COUP site is required for steroid induction, although without the NRE, the COUP site attenuates transcriptional activity. More interestingly, overexpression of COUP-TF1 with the Ov wild-type reporter construct alleviates the requirement for steroid hormones. These results demonstrate that the COUP site is essential and has a dual role in Ov gene transcription and that steroid hormones might directly or indirectly regulate the activity of COUP-TF1.

Animals↗

PubMed1999

Transcriptional activity and regulatory protein binding of metal-responsive elements of the human metallothionein-IIA gene.

Multiple copies of a cis-acting DNA element, metal-responsive element (MRE) are required for heavy metal-induced transcriptional activation of mammalian metallothionein genes. To approach the regulatory mechanism mediated by these multiple elements, we studied the properties of seven MREs located upstream of the human metallothionein-IIA (hMT-IIA) gene in detail. Transfection assays of reporter gene constructs each containing one of these MREs as the promoter element revealed that only four MREs can mediate zinc response. With respect to the distribution of active MREs over the promoter region, the hMT-IIA gene is largely different from the mouse metallothionein-I gene, suggesting that MRE arrangement is not an important factor for metal regulation. Experiments using various model promoters showed that multiple MRE copies act highly synergistically, supporting the biological significance of the multiplicity. Only the four active MREs efficiently bound the purified transcription factor human MTF-1, and MRE mutants defective in binding this protein lost the ability to support zinc-induced reporter gene expression, strongly suggesting that the direct interaction between human MTF-1 and a set of the selected MREs plays the major role in heavy metal regulation. In protein/DNA binding reactions in vitro, the purified human MTF-1 was activated by zinc but not by other metallothionein-inducing heavy metals, supporting the idea that zinc is the direct modulator of human MTF-1.

DNA-Binding Proteins↗

PubMed1998

A pineal regulatory element (PIRE) mediates transactivation by the pineal/retina-specific transcription factor CRX.

The circadian hormone melatonin is synthesized predominantly in the pineal gland by the actions of two pineal-specific enzymes: serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). Pineal night-specific ATPase (PINA), another pineal- and night-specific protein we recently identified, is produced as a truncated form of the Wilson disease gene (Atp7b) product. To identify the regulatory elements required for pineal-specific gene expression, we isolated sequences upstream of the rat PINA gene and discovered a cis-acting element that is recognized by a novel pineal/retina-specific nuclear factor. This pineal regulatory element (PIRE) has a consensus of TAATC/T and is present in six copies in the 5' regulatory region of the PINA gene, at least three copies in the rat NAT promoter, and at least one copy in each of the putative HIOMT promoters A and B. A recently identified retina-specific protein, cone rod homeobox (CRX), binds to PIRE in vitro and transactivates PIRE-reporter constructs. These data suggest that Crx may play a crucial role in regulating pineal gene expression through interactions with PIRE.

Acetylserotonin O-Methyltransferase↗

PubMed1997

The hepatitis B virus posttranscriptional regulatory element contains a highly stable RNA secondary structure.

Hepatitis B virus (HBV) transcripts contain a sequence known as the posttranscriptional regulatory element (PRE). This element was shown to facilitate the nuclear export of the S gene transcripts, to partially substitute for the human immunodeficiency virus (HIV-1) Rev-response element (RRE), and to bind two cellular factors. Within the genetically defined PRE (approximately 450 nucleotides), we identified a highly stable secondary structural element of 313 nucleotides in length termed PRE313. The energy values of the PRE313 are similar to those of the RRE of HIV-1 and significantly lower than those of other portions of HBV RNA. A comparison of human HBV subtypes shows strong conservation of the PRE313 in terms of energy and structure, providing further evidence for the biological significance of the genetically defined PRE and the PRE313 in particular. The structural model for the PRE313 described in this study may help in identifying crucial components of the transport mechanism of transcripts of HBV.

Base Sequence↗

PubMed1994

Architectural variations of inducible eukaryotic promoters: preset and remodeling chromatin structures.

The DNA in a eukaryotic nucleus is packaged into a nucleosome array, punctuated by variations in the regular pattern. The local chromatin structure of inducible genes appears to fall into two categories: preset and remodeling. Preset genes are those in which the binding sites for trans-acting factors are accessible (i.e. in a non-nucleosomal, DNase I hypersensitive configuration) prior to activation. In response to the activation signal, positive factors bind to cis-acting regulatory elements and trigger transcription with no major alterations in the chromatin structure of the promoter region. In contrast, remodeling genes are those in which some of the required cis-acting regulatory elements are packaged into nucleosomes. The nucleosomes must be perturbed in response to an activation signal in order for the trans-acting factors to gain access to cis-acting elements; a chromatin remodeling process which forms DNase I hypersensitive sites must occur. In both cases, precise positioning of nucleosomes along the promoter region of a gene appears to be critical for appropriate regulation of expression.

Animals↗