More help than hindrance

Ballaré, Cecilia; Zaurín, Roser; Vicent, Guillermo P.; Beato, Miguel

doi:10.4161/nucl.25108

Cited by 15 publications

(9 citation statements)

References 24 publications

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“…In addition, the intrinsic DNA sequence played a significant role in determining nucleosome positioning, with approximately 50% of all genes showing changes that were highly correlated with the DNA-directed model. The contribution of DNA sequence to nucleosome position may have implications for gene expression because nucleosome occupancy at conserved noncoding sequences and TFBS is functionally correlated to transcriptional activity in yeast [ 5 ], plant [ 48 ] and human cells [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes

Brown¹,

Vied²,

Dennis³

et al. 2015

PLoS ONE

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Drugs of abuse modify behavior by altering gene expression in the brain. Gene expression can be regulated by changes in DNA methylation as well as by histone modifications, which alter chromatin structure, DNA compaction and DNA accessibility. In order to better understand the molecular mechanisms directing drug-induced changes in chromatin structure, we examined DNA-nucleosome interactions within promoter regions of 858 genes in human neuroblastoma cells (SH-SY5Y) exposed to nicotine or cocaine. Widespread, drug- and time-resolved repositioning of nucleosomes was identified at the transcription start site and promoter region of multiple genes. Nicotine and cocaine produced unique and shared changes in terms of the numbers and types of genes affected, as well as repositioning of nucleosomes at sites which could increase or decrease the probability of gene expression based on DNA accessibility. Half of the drug-induced nucleosome positions approximated a theoretical model of nucleosome occupancy based on physical and chemical characteristics of the DNA sequence, whereas the basal or drug naïve positions were generally DNA sequence independent. Thus we suggest that nucleosome repositioning represents an initial dynamic genome-wide alteration of the transcriptional landscape preceding more selective downstream transcriptional reprogramming, which ultimately characterizes the cell- and tissue-specific responses to drugs of abuse.

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Section: Discussionmentioning

confidence: 99%

Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes

Brown¹,

Vied²,

Dennis³

et al. 2015

PLoS ONE

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“…In fact, compared to wild type NS, the cell viability after VPA was significantly lower in NS with the TC/CC variant genotype. It is well known that nucleosome dense genome regions play a crucial role in controlling the elongation rate of transcription machinery and in regulating access of the promoter to transcription factors [ 35 , 36 ]. Based on the large extension of intron 3 (20491 nt), we speculate that the minor allele C alters the nucleosome genome landscape with subsequent destabilization of exon-intron junctions contributing to remarkable variation of the state–state mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy

Mellai¹,

Cattaneo

Storaci

et al. 2015

Oncotarget

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The suppressor of Lin-12-like (C. elegans) (SEL1L) is involved in the endoplasmic reticulum (ER)-associated degradation pathway, malignant transformation and stem cells.In 412 formalin-fixed and paraffin-embedded brain tumors and 39 Glioblastoma multiforme (GBM) cell lines, we determined the frequency of five SEL1L single nucleotide genetic variants with regulatory and coding functions by a SNaPShot™ assay. We tested their possible association with brain tumor risk, prognosis and therapy.We studied the in vitro cytotoxicity of valproic acid (VPA), temozolomide (TMZ), doxorubicin (DOX) and paclitaxel (PTX), alone or in combination, on 11 GBM cell lines, with respect to the SNP rs12435998 genotype.The SNP rs12435998 was prevalent in anaplastic and malignant gliomas, and in meningiomas of all histologic grades, but unrelated to brain tumor risks. In GBM patients, the SNP rs12435998 was associated with prolonged overall survival (OS) and better response to TMZ-based radio-chemotherapy. GBM stem cells with this SNP showed lower levels of SEL1L expression and enhanced sensitivity to VPA.

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“…Another of the consequences of activation of the c-SRC tyrosine kinase pathway is the phosphorylation of PR and Mitogen- and stress-activated protein kinase-1 (MSK1) by Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). The resulting ternary complex, pPR/pERK/pMSK1 is the active form of the receptor, which interacts with chromatin targets in a subset of target genes [ 34 ]. We observe significant downregulation of MSK1 gene expression by TPA, which may limit the formation of the ternary complex and therefore progesterone-mediated gene expression.…”

Section: Discussionmentioning

confidence: 99%

Progesterone receptor blockade in human breast cancer cells decreases cell cycle progression through G2/M by repressing G2/M genes

et al. 2016

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BackgroundThe synthesis of specific, potent progesterone antagonists adds potential agents to the breast cancer prevention and treatment armamentarium. The identification of individuals who will benefit from these agents will be a critical factor for their clinical success.MethodsWe utilized telapristone acetate (TPA; CDB-4124) to understand the effects of progesterone receptor (PR) blockade on proliferation, apoptosis, promoter binding, cell cycle progression, and gene expression. We then identified a set of genes that overlap with human breast luteal-phase expressed genes and signify progesterone activity in both normal breast cells and breast cancer cell lines.ResultsTPA administration to T47D cells results in a 30 % decrease in cell number at 24 h, which is maintained over 72 h only in the presence of estradiol. Blockade of progesterone signaling by TPA for 24 h results in fewer cells in G2/M, attributable to decreased expression of genes that facilitate the G2/M transition. Gene expression data suggest that TPA affects several mechanisms that progesterone utilizes to control gene expression, including specific post-translational modifications, and nucleosomal organization and higher order chromatin structure, which regulate access of PR to its DNA binding sites.ConclusionsBy comparing genes induced by the progestin R5020 in T47D cells with those increased in the luteal-phase normal breast, we have identified a set of genes that predict functional progesterone signaling in tissue. These data will facilitate an understanding of the ways in which drugs such as TPA may be utilized for the prevention, and possibly the therapy, of human breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2355-5) contains supplementary material, which is available to authorized users.

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More help than hindrance

Cited by 15 publications

References 24 publications

Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes

Nucleosome Repositioning: A Novel Mechanism for Nicotine- and Cocaine-Induced Epigenetic Changes

SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy

Progesterone receptor blockade in human breast cancer cells decreases cell cycle progression through G2/M by repressing G2/M genes

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