1,721,053 research outputs found
The Chromatin-looping Factor ZNF143 is Genetically Altered and Promotes the Oestrogen Response in Breast Cancer
Full text linkOestrogen signalling in breast cancer (BrCa) cells relies on chromatin-loops that connect distal regulatory elements bound by the oestrogen receptor 1 (ESR1) to target gene promoters. We show that chromatin-looping factor genes, including CTCF, ZNF143 and RAD21, are genetically altered in BrCa. Expanding on the function of CTCF and cohesin in BrCa, we demonstrate that ZNF143 binds promoters of most early-response oestrogen target genes connected to distal regulatory elements in ESR1-positive BrCa cells. Its chromatin occupancy is unaffected by oestrogen-stimulation, supporting a stable three-dimensional genomic architecture within the oestrogen response. Its loss abrogates the oestrogen-induced transcriptional response and growth of BrCa cells. Furthermore, we show that the overexpression of looping-factors within ESR-1 positive BrCa patients associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the oestrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive BrCa development.M.Sc
Impact of Noncoding Genetic Alterations on the Cis-regulatory Networks of Prostate Cancer
Full text linkProstate cancer is the second most commonly diagnosed malignancy in men worldwide. While the majority of low-risk patients with localized prostate cancer have favourable outcomes, aggressive intermediate-risk and high-risk patients experience recurrence upon initial treatment and ultimately develop lethal metastatic disease. Hence, there remains a need to better our biological understanding of prostate cancer to improve patient care. Whole-genome sequencing revealed that primary prostate tumours are burdened by thousands of mutations with the majority residing in the noncoding space with unknown function. To address these gaps in our understanding, I investigated the impact of these noncoding mutations by focusing on their involvement in gene regulation through three-dimensional chromatin interactions. I found that mutations enrich at the binding sites of essential transcription factors in prostate cancer genome-wide with a subset that can significantly modulate their binding and drive aberrant activity of cis-regulatory elements. Furthermore, I identified a set of cis-regulatory elements targeted by noncoding mutations
that converge on regulating FOXA1 mRNA expression, a potent prostate cancer oncogene. My work also involved the identification of an enhancer-hijacking event as a result of the TMPRSS2 - ERG fusion that that lead to a subtype-specific cis -regulatory landscape, makingthese cancer cells vulnerable to NOTCH signalling inhibitors. Lastly, through chromatinconformation capture of 12 primary prostate tumour samples, my work revealed novel structural variants that can impact chromatin organization in three-dimensional space. Taken together, my work ascribed functional relevance to noncoding mutations by focusing entities involved in gene regulation through three-dimensional chromatin interactions. Ultimately, my work pushes forward our functional understanding of noncoding mutations that will expand our growing list of oncogenic drivers in prostate cancer and other cancer types.Ph.D
The Chromatin-looping Factor ZNF143 is Genetically Altered and Promotes the Oestrogen Response in Breast Cancer
No full textOestrogen signalling in breast cancer (BrCa) cells relies on chromatin-loops that connect distal regulatory elements bound by the oestrogen receptor 1 (ESR1) to target gene promoters. We show that chromatin-looping factor genes, including CTCF, ZNF143 and RAD21, are genetically altered in BrCa. Expanding on the function of CTCF and cohesin in BrCa, we demonstrate that ZNF143 binds promoters of most early-response oestrogen target genes connected to distal regulatory elements in ESR1-positive BrCa cells. Its chromatin occupancy is unaffected by oestrogen-stimulation, supporting a stable three-dimensional genomic architecture within the oestrogen response. Its loss abrogates the oestrogen-induced transcriptional response and growth of BrCa cells. Furthermore, we show that the overexpression of looping-factors within ESR-1 positive BrCa patients associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the oestrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive BrCa development.M.Sc
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Investigating the role of epigenetic therapy in chemotherapy-resistant triple-negative breast cancer
No full textTriple-negative breast cancer (TNBC) is a highly heterogeneous disease for which effective targeted treatment options are limited. While chemotherapy is currently the standard-of-care therapy, almost half of patients develop chemotherapy resistance, leading to high rates of relapse and poor clinical outcomes. This highlights a need for more effective therapeutic options for chemotherapy-resistant TNBC. To determine the generalizability of the biological mechanisms promoting drug resistance, we developed additional TNBC models that are resistant to the chemotherapy agents, cisplatin, gemcitabine, and eribulin. The prior identification of chromatin variants in this disease state provided rationale for the effective use of epigenetic therapy to circumvent chemotherapy resistance and supported further study into other chromatin-based targets to develop novel treatment regimens. Accordingly, epigenetic drug screening identified candidate targets that are selectively effective against chemoresistant TNBC. Among these, we characterized the synergistic interaction between EZH2 and BRD9/7 inhibitors that abrogates the growth and migration of paclitaxel- and eribulin-resistant TNBC. Mechanistically, we identified that whereas inhibition of type I PRMT triggers the immunogenic viral mimicry response through the induction of double-stranded RNA in certain TNBC models, other epigenetic therapies and chemotherapeutic agents do not elicit viral mimicry in chemosensitive or chemoresistant TNBC. Overall, these data reveal the heterogeneous responses and context-dependent anti-tumoural mechanisms of epigenetic therapy in TNBC.Ph.D
Chromatin Architecture Aberrations Contribute and Acute Lymphoblastic Leukemia Relapse
No full textCancer results from aberrations at the molecular level that enable biological hallmarks. These aberrations can be found within the chromatin architecture of cancer cells that includes the genome, molecular modifications to the genome, and the three-dimensional organization of the chromatin fiber. The majority of genetic variants target non-coding regions of the genome and many genes affected by genetic and epigenetic variants have important roles in chromatin remodelling and maintenance. Thus, understanding the origins of cancer progression requires investigating the targets of these aberrations and how they impact the chromatin architecture.
First, I investigated the impact of non-coding single nucleotide variants that converge on cis-regulatory elements for the FOXA1 gene in primary prostate tumours. We found that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth by altering the potential of transcription factors to bind at these loci. These results identify cis-regulatory elements that control FOXA1 expression in primary prostate cancer as potential targets for therapeutic intervention.
Secondly, I used chromatin conformation capture of 12 primary prostate cancer tumours and 5 benign prostate tissues to characterize the three-dimensional genome organization. We found that large-scale organization, including topologically associated domains and compartments, is largely stable over oncogenesis but that small-scale focal chromatin interactions change between benign and tumour tissue. We also investigated the impact of structural variants on chromatin organization and identify novel enhancer hijacking events. These results indicate that enhancer hijacking of prostate cancer oncogenes may be a more common driver of disease than previously recognized. Then, I developed a statistical framework for differential gene expression analysis to address the impact of non-recurrent structural variants in our primary prostate tumour cohort. This method improves on conventional gene expression fold change estimates in these unbalanced experimental designs.
Finally, I investigated the genetic and epigenetic changes that underlie B-cell acute lymphoblastic leukemia relapse. I found recurrent loss of DNA methylation in patient-matched relapse samples that indicate a more stem-like chromatin state. Together, my work investigates the relationship between multiple components of the chromatin architecture, and how aberrations to this architecture connects oncogenesis, disease progression, and relapse.Ph.D
Epigenetic Vulnerabilities in Triple-Negative Breast Cancer
Full text linkBreast cancer is the most commonly diagnosed cancer amongst Canadian women. To date, three main histopathological subtypes based on the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 with different clinical outcomes dictate the treatment approach. Among these, the Triple-Negative Breast Cancer (TNBC) subtype does not express any of the hormone receptors and has the least survival rate due to lack of targeted therapy and poor prognosis. Recently, a category of highly selective and potent drug-like molecules ideal to assess therapeutic potential of new targets, known as chemical probes, have been designed to target epigenetic enzymes. Here, we determined the impact of 56 epigenetic chemical probes on the proliferation of TNBC cell lines. We identified distinct response across these cell lines after inhibition of the bromodomains, methyltransferases, methyl lysine transferases and lysine demethylases. Our results revealed epigenetic targets that could lead to potential therapeutic opportunities.M.Sc
Epigenetic Vulnerabilities in Triple-Negative Breast Cancer
No full textBreast cancer is the most commonly diagnosed cancer amongst Canadian women. To date, three main histopathological subtypes based on the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 with different clinical outcomes dictate the treatment approach. Among these, the Triple-Negative Breast Cancer (TNBC) subtype does not express any of the hormone receptors and has the least survival rate due to lack of targeted therapy and poor prognosis. Recently, a category of highly selective and potent drug-like molecules ideal to assess therapeutic potential of new targets, known as chemical probes, have been designed to target epigenetic enzymes. Here, we determined the impact of 56 epigenetic chemical probes on the proliferation of TNBC cell lines. We identified distinct response across these cell lines after inhibition of the bromodomains, methyltransferases, methyl lysine transferases and lysine demethylases. Our results revealed epigenetic targets that could lead to potential therapeutic opportunities.M.Sc
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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