MINIREVIEW: A Role for DNA Methylation in Vertebrate Gene Expression?

Strobl, Jeannine S.

doi:10.1210/mend-4-2-181

Cited by 21 publications

(4 citation statements)

References 23 publications

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“…DNA methylation has been identified as one process by which transcription is down-regulated [72]. This process would occur in individual cells of a population and be transmitted to their progeny, leading to progressive cell-specific loss of expression as we see in MKL-4 cells.…”

Section: Problems With Lacz Expressionmentioning

confidence: 70%

Fibroblast growth factor overexpressing breast carcinoma cells as models of angiogenesis and metastasis

McLeskey

Zhang

Kharbanda

et al. 1996

Breast Cancer Res Tr

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Progression of breast cancer from an estrogen-dependent, slowly growing tumor amenable to tamoxifen treatment to an aggressive, metastatic, estrogen-independent phenotype has been mimicked by the transfection of MCF-7 breast carcinoma cells with fibroblast growth factors 1 or 4. FGF-transfected cells are aggressively tumorigenic in ovariectomized or tamoxifen-treated nude mice, conditions under which the parental cells would not produce tumors. When detection of metastasis was enhanced by lacZ transfection, the FGF-transfected MCF-7 cells were reliably metastatic to lymph nodes and frequently metastatic to lungs, in further contrast to parental cells. An antiangiogenic drug, AGM-1470, given to mice bearing tumors produced by FGF-transfected MCF-7 cells, produced a decrease in tumor size. The decreased tumor size was not as marked as that produced by treatment with pentosan polysulfate, an agent which would abrogate all autocrine or paracrine effects of the transfected FGF. Thus, increased angiogenesis may be a component of the phenotypic change produced by the FGF transfection, but other autocrine or paracrine effects may also be important. Since a clonal FGF-4 and lacZ doubly-transfected cell line, MKL-4, progressively lost expression of the transfected lacZ gene in individual cells, we performed successive rounds of fluorescence-activated cell sorting to select high-expressing cells. High-expressing cell populations thus obtained rapidly lost expression of beta-gal activity in continued culture. High beta-gal expressing clonal cell lines of MKL-4 cells established by either one or two rounds of low-density cloning also lost lacZ expression with continued culture. Southern analysis of DNA from lacZ transfected cell lines showed the transfected sequences to be present and grossly intact in both high and low expressing populations. However, Northern analysis revealed that high-expressing populations of MKL-4 cells contained the most lacZ mRNA, implying that in the unstable MKL-4 cell line, individual cells are down-regulating mRNA levels of lacZ. Stable lacZ expression has been obtained in other FGF-transfected and parental MCF-7 cell lines using the same expression vector. Thus, the MKL-4 cell line is down-regulating mRNA encoding the transfected gene through a mechanism not dependent on the CMV promotor utilized in the expression vector. This evidence suggests that lacZ expression is not a benign modification in certain cells.

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Section: Problems With Lacz Expressionmentioning

confidence: 70%

Fibroblast growth factor overexpressing breast carcinoma cells as models of angiogenesis and metastasis

McLeskey

Zhang

Kharbanda

et al. 1996

Breast Cancer Res Tr

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“…As a matter of speculation, we offer the reader one possibility: DNA methylation is a very active process in early development that appears to be associated with the inactivation of genes, a process whereby gene expression is rendered tissue specific [Strobl, 1990]. Thus, the early postnatal period is an active period of DNA methylation.…”

Section: So How Do These Effects Results In the Long-term Differentiatmentioning

confidence: 99%

Early Environmental Regulation of Forebrain Glucocorticoid Receptor Gene Expression: Implications for Adrenocortical Responses to Stress; pp. 61–72

et al. 1996

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The adrenal glucocorticoids and catecholamines comprise a frontline of defense for mammalian species under conditions which threaten homeostasis (conditions commonly referred to as stress). Glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and along with the catecholamines serve to mobilize the production and distribution of energy substrates during stress. The increased secretion of pituitary-adrenal hormones in response to stress is stimulated by the release of corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) from neurons in the nucleus paraventricularis. In this way, a neural signal associated with the stressor is transduced into a set of endocrine and sympathetic responses. The development of the HPA response to stressful stimuli is altered by early environmental events. Animals exposed to short periods of infantile stimulation or handling show decreased HPA responsivity to stress, whereas maternal separation, physical trauma and endotoxin administration enhance HPA responsivity to stress. In all cases, these effects persist throughout the life of the animal and are accompanied by increased hypothalamic levels of the mRNAs for CRH and often AVP. The inhibitory regulation of the synthesis for these ACTH releasing factors is achieved, in part, through a negative feedback loop whereby circulating glucocorticoids act at various neural sites to decrease CRH and AVP gene expression. Such inhibitory effects are initiated via an interaction between the adrenal steroid and an intracellular receptor (either the mineralocorticoid or glucocorticoid receptor). We have found that these early environmental manipulations regulate glucocorticoid receptor gene expression in the hippocampus and frontal cortex, regions that have been strongly implicated as sites for negative-feedback regulation of CRH and AVP synthesis. When the differences in glucocorticoid receptor density are transiently reversed, so too are those in HPA responses to stress. Taken together, our findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons. This effect involves an altered rate of glucocorticoid receptor gene expression, resulting in changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and AVP in hypothalamic neurons. Changes in CRH and AVP levels, in turn, determine the responsivity of the axis to subsequent stressors; increased releasing factor production is associated with increased HPA responses to stress. Thus, the early environment can contribute substantially to the development of stable individual differences in HPA responsivity to stressful stimuli. These data provide examples of early environmental programming of neural systems. One major objective of our research is to understand how such programming occurs within the brain.

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“…However, more subtle epigenetic alterations could also occur, including alterations to patterns of DNA methylation. DNA methylation plays an important role in regulation of eukaryotic gene expression [34] and alterations to methylation patterns can be associated with many disease processes including cancer [35]. It has been shown recently that gene-specific promoter methylation can be modulated by carcinogen exposure [36] and that abnormal demethylation of genes can result from neonatal exposure to I998 diethylstilboestrol [37].…”

Section: Alterations To Dnamentioning

confidence: 99%

Environmental contaminants in milk: the problem of organochlorine xenobiotics

Darbre

1998

Biochemical Society Transactions

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MINIREVIEW: A Role for DNA Methylation in Vertebrate Gene Expression?

Cited by 21 publications

References 23 publications

Fibroblast growth factor overexpressing breast carcinoma cells as models of angiogenesis and metastasis

Fibroblast growth factor overexpressing breast carcinoma cells as models of angiogenesis and metastasis

Early Environmental Regulation of Forebrain Glucocorticoid Receptor Gene Expression: Implications for Adrenocortical Responses to Stress; pp. 61–72

Environmental contaminants in milk: the problem of organochlorine xenobiotics

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