NCube/papyrus huggingface dataset:
Mechanisms of transcriptional repression by pure antiestrogens in breast cancer cells

70% of breast tumours express the estrogen receptor ERα, and their growth is regulated by estrogens. Antiestrogens (AEs) such as tamoxifen are used to treat all stages of ER-positive breast cancers, but can present partial agonist activity in a gene- and cell type-specific manner. Pure AEs like fulvestrant (ICI182,780) are prescribed to treat advanced ER-positive breast cancer in patients resistant to tamoxifen. Pure AEs lead to the degradation of ERα via the ubiquitin – proteasome pathway, but these compounds can repress ERα activity independently of receptor degradation. Our laboratory previously published that pure AEs induce SUMOylation of ERα, and abrogation of this post-translational modification increased transcriptional activity of ERα on a reporter vector in transfected cells. We hypothesize that SUMOylation of ERα contributes to the fuller antagonist profile of fulvestrant compared to tamoxifen in breast cancer cells, by repressing transcription of ERα target genes via modulated cofactor recruitment in the presence of pure AEs.  Our work shows that fulvestrant induces a rapid initial ERα binding to its target sequences in the genome. The loss of binding to DNA at longer time points of treatment is independent from ERα degradation and is not due to nuclear export of the receptor, but is accompanied by chromatin compaction. SUMO marks were detected on estrogen response elements after treatment with pure AEs in a manner correlating with the presence of the receptor. Overexpression of a deSUMOylase delays the kinetics of loss of binding to DNA, attenuates chromatin closure and de-represses ER target gene expression in the presence of fulvestrant. Finally, ERα mutations preventing its SUMOylation also lead to de-repression of ER target gene expression specifically in the presence of fulvestrant.  Using a proteomics approach, we further identified the pure AE-induced SUMO-dependent recruitment of the ACF chromatin remodelling complex to ER target regions in the genome. Knockdown of the ACF1 subunit abrogates chromatin compaction and de-represses ER target gene expression in the presence of fulvestrant, linking ACF recruitment with pure AE antagonsim. ERα mutants non-permissive for SUMOylation do not recruit ACF and remain bound to DNA following prolonged fulvestrant treatment, allowing weak transcription of ER target genes.  We propose a model whereby pure AEs induce SUMOylation of ERα, leading to the rapid recruitment of the ACF chromatin remodelling complex to the regulatory regions of estrogen target genes. The resulting chromatin compaction prohibits further ERα recruitment to DNA and contributes to a complete transcriptional shut-off of estrogen signalling in breast cancer cells.

Keyphrases: SUMOylation, Complexe ACF, Breast cancer, Estrogen receptor alpha, Pure antiestrogens, SUMOylation, Transcriptional repression, Chromatin remodelling, ACF complex
Neuraminidases as triggers of atherosclerosis

Atherosclerosis is a chronic vascular disease characterized by lipid retention and inflammation in the vessel wall. Atherosclerosis of the coronary arteries (Coronary Artery Disease or CAD) is the leading current cause of death worldwide. The disease is triggered by the uptake by resident macrophages of low-density lipoproteins (LDL) forming arterial fatty streaks and eventually atheromatous plaques. Our recent data suggest that enzymes of the neuraminidase (sialidase) family, present on the surface of hematopoietic cells and arterial endothelium, also contribute to atherosclerosis. These enzymes are involved in removal of sialic acids (Sia) from glycan chains of glycoproteins and glycolipids, modulating molecular and cellular recognition as well as cellular signaling pathways. Previously human neuraminidases (Neu1, Neu2, Neu3, and Neu4) were not considered to be clinical targets for prevention or treatment of atherosclerosis, but we found that desialylation of a major LDL glycoprotein – apolipoprotein B 100 (ApoB) in human LDL by Neu1 or Neu3 increases LDL uptake by cultured human macrophages and leads to accumulation of LDL in the aortic wall of live mice. We further showed that in a murine model of atherosclerosis, Apolipoprotein E (ApoE) knockout mice, genetic deficiency of Neu1 and Neu3 significantly delayed the formation of fatty streaks in the aortic root. We suggest that neuraminidase inhibition-based therapies merit clinical evaluation for treating or preventing atherosclerosis and coronary artery disease.

Keyphrases: Atherosclerosis, Coronary artery disease, Neuraminidase, Sialic acid, Low-density lipoproteins, Apolipoprotein B 100, Neuraminidases
Impact des variants génétiques sur la réponse immunitaire des populations humaines

The mechanisms that explain inter-individual and population differences in susceptibility to infectious diseases remain poorly understood. During my PhD, I uncovered important variabilities in the immune response to pathogens between individuals of African and European descent. We observed that 34% of genes expressed in macrophages show at least one type of ancestry-related transcriptional divergence, whether in the form of differences in gene expression (30%), the transcriptional response to infection (9.3%), or, less commonly, differences in isoform usage (1%). African ancestry also specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Among those variants, I identified several signatures of natural selection suggesting that pathogens were involved in the adaptation of our species to fluctuating pathogenic realities, contributing therefore to the recent evolution of our immune system. I also showed that admixture between our species and Neandertals played a significant role in the adaptation of non-African populations to the new pathogenic environments modern humans had to face when leaving the Africa to colonize the globe.

Keyphrases: Immunity, Infection, Population genetics, Genomics, Sequencing, Genetic variants, Precision medicine
Caractérisation de la régulation des nouvelles cibles transcriptionnelles du facteur de transcription ETV6 dans la leucémie lymphoblastique aiguë

B-cells acute lymphoblastic leukemia (B-ALL) accounts for 22% of all childhood cancer cases. Among the genetic aberrations identified in B-ALL, the translocation t(12;21)(p13;q22) is the most frequent one. This translocation generates a chimeric protein between the transcription factors ETV6 and RUNX1. Although some oncogenic phenotypes have been associated to ETV6-RUNX1, its presence alone is not sufficient to induce leukemogenesis. The deletion of the 12p13 locus bearing the ETV6 gene is observed in approximately 70% of t(12;21) positive B-ALL cases, suggesting that the complete inactivation of ETV6 is a complementary event required for leukemic transformation. Despite the high occurrence of ETV6 abnormalities observed in hematological disorders, few studies have focused on its molecular function. To better understand the impact of ETV6 inactivation in B-ALL, I used expression data from leukemic cell lines and patients to identify its transcriptional targets. Together with the mapping of ETV6 binding sites obtained from chromatin immunoprecipitation experiments, I constructed its regulatory network and highlight the complexity of its transcriptional function. Functional studies have unveiled a new function for the CLIC5 target gene in protecting cells against oxidative stress.  To further characterize ETV6 at the molecular level, I designed a genome wide shRNA screen and identified genes involved in its transcriptional function. The impact of some of these genes on ETV6 transcriptional network confirmed their role as modulators. In this regard, AKIRIN1, COMMD9, DYRK4, JUNB and SRP72 are broad modulators of ETV6 function whereas some others act specifically on certain targets. This study is the first to have focused on genes involved in the functional regulation of ETV6 in leukemia. The results obtained throughout this thesis have greatly improved our knowledge of the ETV6 transcription factor in B-ALL. The integration of various approaches has highlighted the complexity of its regulation and will allow a better understanding of the mechanisms underlying its role in hematological disorders.

Keyphrases: Childhood acute lymphoblastic leukemia, ETV6 transcription factor, Transcriptional regulation, DNA binding, Functional modulators
L’étude de la glycoprotéine gM du virus Herpès simplex de type 1 (HSV-l) : identification de ses partenaires viraux et cellulaires et leur rôle dans la régulation de l’infection virale

Herpes simplex virus type 1 (HSV-1) is an important human pathogen that causes a variety of diseases ranging from mild skin disorders to fatal encephalitis. HSV-1 virions are constituted of an icosahedral DNA-containing capsid that is surrounded by a lipid envelope. The surface of the viral envelope is decorated with an array of glycoprotein spikes. Glycoprotein M, (gM) encoded by UL10, is considered as a non-essential glycoprotein, however is highly conserved throughout the herpesvirus family. In the course of infection, gM is expressed at both early late stages of the viral life cycle. This protein can localize in different membranous compartments, and is able to modulate virus-induced membrane fusion. This property, most certainly implies the interaction of gM with other viral and cellular proteins. Therefore, it prompted us to identify and characterize gM viral and cellular interacting partners and its regulatory functions during viral infection.  The first article presented in this thesis has been published in Journal of Virology and focuses on HSV-1 gM/gN complex, which has been documented in several herpesviruses but this has not yet been demonstrated for HSV-1. As a part of this study, we examined the putative interaction of gM / gN. We confirmed that gM and gN complex and their interaction is sufficient for gN to transport from the ER to the TGN. Furthermore, we showed that the overexpression of gN during the infection stimulates the formation of syncytia indicating that gM and gN not only interact physically but also functionally. This suggests a role of gN in membrane fusion. These results contributed to a better understanding of the role of gM/gN complex as a new fusion modulator in viral fusion.  In the second article presented in this thesis, we set out to identify potential cellular partners of gM, using an immunoprecipitation (IP) assay combined with mass spectrometry (MS/MS). We identified the Extended synaptotagmin-1 (E-Syt1) as a gM interacting partner. Next, this interaction was confirmed by co-immunoprecipitation in transfected cells and also in the context of infection. Moreover, by using small interfering RNAs (siRNA) specifically targeting E-Syt1 and/or E-Syt3, we were able to show that these proteins negatively regulate the entry, egress and the cell-to-cell spread of the virus. Manipulating the expression of E-Syt 1 and /or E-Syt3 disrupts HSV-1 replication and demonstrates the interaction between cellular and viral fusion machinery.

Keyphrases: E-Syt1, E-Syt3, Fusion, gM, gN, HSV-1, Syncytia
Identifier et cibler les meilleurs antigènes pour l’immunothérapie du cancer

In a context where adoptive transfer of T lymphocytes (ATC) represents the future of cancer immunotherapy, the identification of the best antigens associated to major histocompatibility complex class I (MAPs) to target on cancer cells is of capital importance. Several types of MAPs expressed at the surface of cancer cells can be targeted for ATC: 1) minor histocompatibility antigens (MiHAs), that derive from germline polymorphisms between a donor and a recipient during an ATC, 2) tumor associated antigens (TAAs) that include antigens that derive from overexpressed transcripts in cancer cells compared to their normal counterpart and 3) tumor specific antigens (TSAs) that derive from somatic mutations or from aberrantly expressed transcripts in cancer cells. Hundreds of clinical trials have highlighted the therapeutic potential of each of these classes of antigens. Nonetheless, ATCs targeting these antigens have been studied in dramatically different contexts: donor-derived T cells targeting MiHAs are used for treating hematologic malignancies while patient-derived T cells targeting TAAs or TSAs are used for the treatment of solid tumors. As such, the therapeutic potential of these MAPs has never been assessed in a single tumor model. Thus, the goal of this thesis was to evaluate and compare the therapeutic potential of MiHAs, TAAs and TSAs expressed on the EL4 cell line to better understand the mechanisms dictating their immunogenicity. We first selected MiHAs and TAAs previously reported in the literature, then developed a proteogenomic approach that enabled us to identify all types of TSAs presented by EL4 cells. By doing so, we found that : 1) Only MAPs that are seen as non-self by T cells (MiHAs and TSAs) can induce strong antitumor responses, 2) Both the abundance and functional avidity of MiHA- or TSA-specific T cells dictated the immunogenicity of these antigens, and 3) The clonality of the antigen and the nature of their genetic alterations also represented an important parameter dictating TSAs’ immunogenicity. In conclusion, we developed a proteogenomic platform that will enable the identification of all types of cancer antigens and identified metrics that will guide the priorization of MiHAs and TSAs in a clinical setting.

Keyphrases: Major histocompatibility complex class I, Immunotherapy, T lymphocyte, Minor histocompatibility antigens, Tumor associated antigens, Tumor specific antigens, Mass spectrometry, RNA sequencing, Proteogenomic
Repenser le mythe de l'androgyne dans le Banquet de Platon

The Androgynous Myth in Plato’s Symposium is one of the readers’ favourites, but we have several reasons to believe that Plato didn’t adhere to it at all. Indeed, he made this tale pronounced by the character Aristophanes, whom he had many reasons to hate. Moreover, he mocks Aristophanes, giving him hiccups in the dialogue, keeping him from talking after Pausanias, as planned. Furthermore, when Socrates presents Diotima’s teaching in his speech, he directly makes references to the Androgynous Myth to criticize it. However, this does not mean that Plato rejects all the elements of Aristophanes’ myth. A careful reading of the Symposium reveals that there are narrow links between the two speeches. In this essay, we shall try to demonstrate that the widespread opinion is wrong about the poet’s discourse. Plato’s philosopher is nobody, but Aristophanes’ troubled lover.

Keyphrases: Aristophane, Socrate, Philosophy, Plato, Symposium, Aristophanes, Love, Androgynous, Socrates, Diotima
Le rôle de la performativité dans la méthode de Michel Foucault

Starting from the problematic relationship of Foucault towards Austin’s performativity, this research investigates the methodological evolutions of the archeology and genealogy while looking at the elements imported from the speech act theory. If the knowledges that depict Foucault’s early works are producing a series of effects into reality, it is because the analysis of discourse discovers a new level of performativity in comparison to Austin’s performative utterances: the anonymous discourses generate effects of power through their own descriptive functions. In a similar way, the later analysis of subjectivation procedures shows how inside the articulation of knowledge and power the relationship to the self is a key element of discourse: the subject must recite and adhere to precise types of utterances to produce and establish his subjectivity. Such foundation is the correlate of a third level of performativity where the discourse of the self must be held by the subject and on himself, in other words a performativity of subjectivation.

Keyphrases: John Langshaw Austin, Discours, Performativity, archeology, genealogy, power, technique of the self, subjectivity, speech act
Identification of novel regulators of estrogen receptor alpha signalling and proliferation in breast cancer

Breast cancer remains the most commonly diagnosed cancer among women, with one in nine Canadian women expected to be diagnosed within her lifetime. Breast cancer is a heterogeneous disease, and stratification of patients into cohorts based on the expression of the molecular markers estrogen receptor α (ERα), progesterone receptor (PR) and/or HER2 helps dictate choice of therapy and predict disease prognosis. Over 70% of breast tumours express ERα, a ligand-inducible transcription factor. Stimulation with estradiol (E2) leads to receptor binding to estrogen response elements (ERE) in target gene regulatory sequences in association with transcription cofactors, and results in altered gene expression, increased cell proliferation and accelerated tumour growth. While a number of pathways have been shown to influence ERα signalling, an exhaustive study of genes affecting ERα signalling has not yet been published.  In this study, we describe the design, optimization and execution of an arrayed genome-wide shRNA screening protocol to identify genes modulating ERα expression, signalling and E2-dependent proliferation in a human ERα-positive luminal breast cancer cell line stably expressing a luciferase reporter under the control of an estrogen-responsive promoter. We have validated our screening assays by monitoring the effects of ERα knockdown and knockdown of the known ERα cofactor, NRIP1, as a proof of principle.   Our screen confirmed a number of known regulators of ERα signalling (NCOA1, NCOA2, NRIP1, FOXA1 and GATA3). We also identified several novel regulators of ERα expression, including the lysine acetyl transferase, KAT6A. Knockdown of KAT6A decreased the expression of ERα transcript and protein, and led to gene expression patterns comparable to those obtained following ERα knockdown. In addition, we identified a number of candidate regulators of ERα signalling, including the chromatin assembly complex CHRAC. Knockdown of CHRAC1 resulted in a strong repressive effect on estrogen target genes included those involved in cell cycle control, cell proliferation and DNA repair, and decreased proliferation of our model cell line.  This study gives insight into previously unknown genes and molecular signalling pathways affecting expression and/or transcriptional activity of ERα and proliferation of ERα-positive cancer cells, and provides novel avenues to explore to prevent and/or circumvent antiestrogen resistance.

Keyphrases: ERα, Breast cancer, Proliferation, Estrogen receptor, High-throughput screening
Le surhomme dans l'oeuvre de Nietzsche

Nietzsche's philosophy is characterized by two features: the fight against idealism and the quest for a higher type of man. The word by which Nietzsche refers to his ideal is the "superman". It appears during the Thus Spoke Zarathustra period, is eclipsed for a while, and reappears in the writings of the late period, particularly in Antichrist and Ecce Homo. At each stage of this route, the context in which the concept is embedded highlights its different characteristics. As part of this work we will focus on the passages where he appears explicitly. By isolating it in this way, we can better study it and see the authentic relations in which he was conceived. At the end of the course, it will appear that the superman differs from man as he was until now by its ability to affirm reality. The formula that sums up this attitude is that of « amor fati ». The formula serves as basis for the proclamation of a new order of values determined by the rejection of all idealism.

Keyphrases: Nietzsche, Amor fati, Overman, Idealism, Eternal recurrence
Le sens dans la vie revisité par Susan Wolf

“What gives my life meaning?”  This question reaches new perspectives with the work of the philosopher Susan Wolf. The purpose of my master’s thesis is to present the account of Susan Wolf’s in Meaning in Life and why it matters and to discuss the interest and the limits of the conditions that she exposes. Wolf distinguishes two dimensions of an action (or an engagement, interest or project) that gives meaning: the subjective and the objective. They are both required as conditions that an action must fulfill to possibly contributes to the meaningfulness of a person’s life: «Meaning arises when subjective attraction meets objective attractiveness» (Wolf, 1997, 305; Wolf, 2010, 9). Thus, her account invites us to recognize new reasons in normative ethics to justify an action. These are “reasons of love”. According to Wolf, this type of reason bears its own legitimacy and cannot be reduced nor be subsumed under the concepts of happiness or morality, essentially because it has an intrinsic value. The implications of this theory open the way both to a better understanding of the human being and to a conception of the good life which is more inclusive in normative ethics. Wolf suggest that no one can tell another what should give meaning to their life, but each one must develop the reflexive capacity that permits the narrative and subjective endorsement of what makes his life better and meaningful as well. And that’s the role of philosophy.

Keyphrases: Susan Wolf, meaning, meaningfulness, value, ethics, reasons of love, love, philosophy, normativity, objectivity
L’Éthique non-géométrique de Spinoza

The Ethics by Spinoza, demonstrated in geometrical order (more geometrico demonstrata), faces the issue of introducing the non-geometrician reader to the objective content of its knowledge. Although his philosophy is in its majority exposed within a mathematical structure, this paper aims to study the intrinsically non demonstrative elements that reside therein and therefore determine the propaedeutics dimension of the Ethics, i.e. its capacity to bring an individual enslaved by passions into an ethical becoming. From a methodological point of view, and after exposing the euclidian origins of spinozism, we will defend the idea that scolies, resonating with an affective order of knowledge, fulfil a pedagogical function relying mostly on the virtues of imagination. Consequently, it will then be argued that imagination is a means of knowledge that is inherently positive. It is capable of producing joyful affects, an observation from which Spinoza conceived the possibility of accessing, through common notions, knowledge of the second kind and a life guided by reason. Thus we will show how the ruling principles of spinozistic anthropology explain the epistemological problem of the passage between these different kinds of knowledge. Finally, we shall see that it is through a pragmatic use of language - that is to say a language that encompasses in its expression the recipients’ multiple levels of comprehension - that the philosopher allows the Ethics to become a place of passionate confluence whose specificity is to introduce the non philosopher to the emancipating virtues of true knowledge.

Keyphrases: Scolie, Imagination, Affect, Joie, Spinoza, Philosophy, Common notion, Joy