81 results found
Varghese V, Magnani L, Harada N, et al., 2015, Inhibition of FOXM1 by thiostrepton increases sensitivity to 5-fluorouracil (5-FU) by downregulating thymidylate synthase (TS) in colorectal cancer, AACR Precision Medicine Conference on Drug Sensitivity and Resistance - Improving Cancer Therapy, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Brown R, Curry E, Magnani L, et al., 2014, Poised epigenetic states and acquired drug resistance in cancer, Nature Reviews Cancer, Vol: 14, Pages: 747-753, ISSN: 1474-1768
Varghese V, Magnani L, Harada N, et al., 2014, Forkhead box transciption factor M1 (FOXM1) plays a critical role in colorectal cancer resistance by regulating thymidylate synthase (TS), 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Jangal M, Couture J-P, Bianco S, et al., 2014, The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor alpha target genes, Nucleic Acids Research, Vol: 42, Pages: 11339-11348, ISSN: 1362-4962
Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in breast cancer MCF-7 cells, TLE3, a co-repressor of the Groucho/Grg/TLE family, interacts with FoxA1 and is detected at regulatory elements of ERα target genes in absence of estrogen. As a result, the chromatin is maintained in a basal state of acetylation, thus preventing ligand-independent activation of transcription. In absence of TLE3, the basal expression of ERα target genes induced by E2 is increased. At the TFF1 gene, the recruitment of TLE3 to the chromatin is FoxA1-dependent and prevents ERα and RNA polymerase II recruitment to TFF1 gene regulatory elements. Moreover, the interaction of TLE3 with HDAC2 results in the maintenance of acetylation at a basal level. We also provide evidence that TLE3 is recruited at several other regulatory elements of ERα target genes and is probably an important co-regulator of the E2 signaling pathway. In sum, our results describe a mechanism by which TLE3 affects ligand dependency in ERα-regulated gene expression via its binding restricting function and its role in gene regulation by histone acetylation.
Magnani L, 2014, Epigenetic engineering and the art of epigenetic manipulation, Genome Biology, Vol: 15, ISSN: 1474-760X
This short and focused meeting was set up to bring the audience up to date with a specific set of techniques broadly categorized as epigenetic engineering (or epigenetic editing). The speakers reminded us of very important questions that still linger, like Damocles’ sword, over the field of epigenetics: what is the real role of epigenetics during gene transcription and development? Are epigenetic modifications the cause or consequence of these processes? While the jury is still out, this meeting reminded us that the tools needed to answer these philosophical questions are finally available and improving by the hour. Moreover, there was also a general consensus that epigenetic editing might provide the next big advance in cancer treatment. Epigenetic-editing treatments might finally allow targeted modulation of gene expression and could bypass the side effects of current epigenetic drugs.
Lombardo Y, Faronato M, Filipovic A, et al., 2014, Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells, Breast Cancer Research, Vol: 16, ISSN: 1465-542X
IntroductionResistance to anti-estrogen therapies is a major cause of disease relapse and mortality in estrogen receptor alpha (ERα)-positive breast cancers. Tamoxifen or estrogen withdrawal increases the dependence of breast cancer cells on Notch signalling. Here, we investigated the contribution of Nicastrin and Notch signalling in endocrine-resistant breast cancer cells.MethodsWe used two models of endocrine therapies resistant (ETR) breast cancer: tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF7 cells. We evaluated the migratory and invasive capacity of these cells by Transwell assays. Expression of epithelial to mesenchymal transition (EMT) regulators as well as Notch receptors and targets were evaluated by real-time PCR and western blot analysis. Moreover, we tested in vitro anti-Nicastrin monoclonal antibodies (mAbs) and gamma secretase inhibitors (GSIs) as potential EMT reversal therapeutic agents. Finally, we generated stable Nicastrin overexpessing MCF7 cells and evaluated their EMT features and response to tamoxifen.ResultsWe found that ETR cells acquired an epithelial to mesenchymal transition (EMT) phenotype and displayed increased levels of Nicastrin and Notch targets. Interestingly, we detected higher level of Notch4 but lower levels of Notch1 and Notch2 suggesting a switch to signalling through different Notch receptors after acquisition of resistance. Anti-Nicastrin monoclonal antibodies and the GSI PF03084014 were effective in blocking the Nicastrin/Notch4 axis and partially inhibiting the EMT process. As a result of this, cell migration and invasion were attenuated and the stem cell-like population was significantly reduced. Genetic silencing of Nicastrin and Notch4 led to equivalent effects. Finally, stable overexpression of Nicastrin was sufficient to make MCF7 unresponsive to tamoxifen by Notch4 activation.ConclusionsETR cells express high levels of Nicastrin and Notch4, whose activation ultimately drives invasive be
Bianco S, Brunelle M, Jangal M, et al., 2014, LRH-1 Governs Vital Transcriptional Programs in Endocrine-Sensitive and -Resistant Breast Cancer Cells, CANCER RESEARCH, Vol: 74, Pages: 2015-2025, ISSN: 0008-5472
Gadaleta RM, Magnani L, 2014, Nuclear receptors and chromatin: an inducible couple, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 52, Pages: R137-R149, ISSN: 0952-5041
Magnani L, Lupien M, 2014, Chromatin and epigenetic determinants of estrogen receptor alpha (ESR1) signaling, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 382, Pages: 633-641, ISSN: 0303-7207
Magnani L, Stoeck A, Zhang X, et al., 2013, Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: E1490-E1499, ISSN: 0027-8424
Magnani L, Brunelle M, Gevry N, et al., 2012, Chromatin landscape and endocrine response in breast cancer, EPIGENOMICS, Vol: 4, Pages: 675-683, ISSN: 1750-1911
Thiaville MM, Stoeck A, Chen L, et al., 2012, Identification of PBX1 target genes in cancer cells by global mapping of PBX1 binding sites, PLOS One, Vol: 7, ISSN: 1932-6203
PBX1 is a TALE homeodomain transcription factor involved in organogenesis and tumorigenesis. Although it has been shown that ovarian, breast, and melanoma cancer cells depend on PBX1 for cell growth and survival, the molecular mechanism of how PBX1 promotes tumorigenesis remains unclear. Here, we applied an integrated approach by overlapping PBX1 ChIP-chip targets with the PBX1-regulated transcriptome in ovarian cancer cells to identify genes whose transcription was directly regulated by PBX1. We further determined if PBX1 target genes identified in ovarian cancer cells were co-overexpressed with PBX1 in carcinoma tissues. By analyzing TCGA gene expression microarray datasets from ovarian serous carcinomas, we found co-upregulation of PBX1 and a significant number of its direct target genes. Among the PBX1 target genes, a homeodomain protein MEOX1 whose DNA binding motif was enriched in PBX1-immunoprecipicated DNA sequences was selected for functional analysis. We demonstrated that MEOX1 protein interacts with PBX1 protein and inhibition of MEOX1 yields a similar growth inhibitory phenotype as PBX1 suppression. Furthermore, ectopically expressed MEOX1 functionally rescued the PBX1-withdrawn effect, suggesting MEOX1 mediates the cellular growth signal of PBX1. These results demonstrate that MEOX1 is a critical target gene and cofactor of PBX1 in ovarian cancers.
Wang X, Park K-E, Koser S, et al., 2012, KPNA7, an oocyte- and embryo-specific karyopherin alpha subtype, is required for porcine embryo development, REPRODUCTION FERTILITY AND DEVELOPMENT, Vol: 24, Pages: 382-391, ISSN: 1031-3613
Magnani L, Eeckhoute J, Lupien M, 2011, Pioneer factors: directing transcriptional regulators within the chromatin environment, TRENDS IN GENETICS, Vol: 27, Pages: 465-474, ISSN: 0168-9525
Magnani L, Ballantyne EB, Zhang X, et al., 2011, PBX1 Genomic Pioneer Function Drives ER alpha Signaling Underlying Progression in Breast Cancer, PLOS GENETICS, Vol: 7, ISSN: 1553-7404
Wang K, Sengupta S, Magnani L, et al., 2010, Brg1 is required for Cdx2-mediated repression of Oct4 expression in mouse blastocysts, PLOS One, Vol: 5, ISSN: 1932-6203
During blastocyst formation the segregation of the inner cell mass (ICM) and trophectoderm is governed by the mutually antagonistic effects of the transcription factors Oct4 and Cdx2. Evidence indicates that suppression of Oct4 expression in the trophectoderm is mediated by Cdx2. Nonetheless, the underlying epigenetic modifiers required for Cdx2-dependent repression of Oct4 are largely unknown. Here we show that the chromatin remodeling protein Brg1 is required for Cdx2-mediated repression of Oct4 expression in mouse blastocysts. By employing a combination of RNA interference (RNAi) and gene expression analysis we found that both Brg1 Knockdown (KD) and Cdx2 KD blastocysts exhibit widespread expression of Oct4 in the trophectoderm. Interestingly, in Brg1 KD blastocysts and Cdx2 KD blastocysts, the expression of Cdx2 and Brg1 is unchanged, respectively. To address whether Brg1 cooperates with Cdx2 to repress Oct4 transcription in the developing trophectoderm, we utilized preimplantation embryos, trophoblast stem (TS) cells and Cdx2-inducible embryonic stem (ES) cells as model systems. We found that: (1) combined knockdown (KD) of Brg1 and Cdx2 levels in blastocysts resulted in increased levels of Oct4 transcripts compared to KD of Brg1 or Cdx2 alone, (2) endogenous Brg1 co-immunoprecipitated with Cdx2 in TS cell extracts, (3) in blastocysts Brg1 and Cdx2 co-localize in trophectoderm nuclei and (4) in Cdx2-induced ES cells Brg1 and Cdx2 are recruited to the Oct4 promoter. Lastly, to determine how Brg1 may induce epigenetic silencing of the Oct4 gene, we evaluated CpG methylation at the Oct4 promoter in the trophectoderm of Brg1 KD blastocysts. This analysis revealed that Brg1-dependent repression of Oct4 expression is independent of DNA methylation at the blastocyst stage. In toto, these results demonstrate that Brg1 cooperates with Cdx2 to repress Oct4 expression in the developing trophectoderm to ensure normal development.
Park K-E, Johnson CM, Magnani L, et al., 2010, Global H3K9 Dimethylation Status Is Not Affected by Transcription, Translation, or DNA Replication in Porcine Zygotes, MOLECULAR REPRODUCTION AND DEVELOPMENT, Vol: 77, Pages: 420-429, ISSN: 1040-452X
Dinelli BM, Arnone E, Brizzi G, et al., 2010, The MIPAS2D database of MIPAS/ENVISAT measurements retrieved with a multi-target 2-dimensional tomographic approach, ATMOSPHERIC MEASUREMENT TECHNIQUES, Vol: 3, Pages: 355-374, ISSN: 1867-1381
Park K-E, Magnani L, Cabot RA, 2009, Differential Remodeling of Mono- and Trimethylated H3K27 During Porcine Embryo Development, MOLECULAR REPRODUCTION AND DEVELOPMENT, Vol: 76, Pages: 1033-1042, ISSN: 1040-452X
Xing X, Magnani L, Lee K, et al., 2009, Gene Expression and Development of Early Pig Embryos Produced by Serial Nuclear Transfer, MOLECULAR REPRODUCTION AND DEVELOPMENT, Vol: 76, Pages: 555-563, ISSN: 1040-452X
Carlotti M, Magnani L, 2009, Two-dimensional sensitivity analysis of MIPAS observations, OPTICS EXPRESS, Vol: 17, Pages: 5340-5357, ISSN: 1094-4087
Wang X, Magnani L, Cabot R, 2009, KARYOPHERIN alpha EXPRESSION IN PORCINE OOCYTES AND EMBRYOS PRODUCED BY IN VITRO FERTILIZATION, REPRODUCTION FERTILITY AND DEVELOPMENT, Vol: 21, Pages: 197-198, ISSN: 1031-3613
Biancardi MN, Magnani L, Johnson CM, et al., 2009, TRANSCRIPT ABUNDANCE OF METHYLTRANSFERASES SPECIFIC FOR H3K9 DIFFER AT DISCRETE STAGES OF PORCINE OOCYTE AND CLEAVAGE STAGE EMBRYO DEVELOPMENT, REPRODUCTION FERTILITY AND DEVELOPMENT, Vol: 21, Pages: 188-188, ISSN: 1031-3613
Magnani L, Cabot RA, 2009, Manipulation of SMARCA2 and SMARCA4 transcript levels in porcine embryos differentially alters development and expression of SMARCA1, SOX2 NANOG, and EIF1, REPRODUCTION, Vol: 137, Pages: 23-33, ISSN: 1470-1626
Magnani L, Cabot RA, 2008, In Vitro and In Vivo Derived Porcine Embryos Possess Similar, but Not Identical, Patterns of Oct4, Nanog, and Sox2 mRNA Expression During Cleavage Development, MOLECULAR REPRODUCTION AND DEVELOPMENT, Vol: 75, Pages: 1726-1735, ISSN: 1040-452X
Xing X, Magnani L, Lee K, et al., 2008, Gene expression in early porcine embryos following serial nuclear transfer, 16th International Congress on Animal Reproduction, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 7-7, ISSN: 0936-6768
Magnani L, Lee K, Fodor WL, et al., 2008, Developmental capacity of porcine nuclear transfer embryos correlate with levels of chromatin-remodeling transcripts in donor cells, MOLECULAR REPRODUCTION AND DEVELOPMENT, Vol: 75, Pages: 766-776, ISSN: 1040-452X
Park K, Magnani L, Cabot R, 2008, Expression patterns of H3/K27 methylation mediating genes in porcine embryos, 41st Annual Meeting of the Society-for-the-Study-of-Reproduction, Publisher: SOC STUDY REPRODUCTION, Pages: 96-97, ISSN: 0006-3363
Magnani L, Cabot R, 2008, Ectopic expression of Brahma in porcine embryos induces developmental arrest and alters expression of SNF2L, 41st Annual Meeting of the Society-for-the-Study-of-Reproduction, Publisher: SOC STUDY REPRODUCTION, Pages: 72-72, ISSN: 0006-3363
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