An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Les facteurs de transcription Sox contrôlent le développement des canaux biliaires

Liver tissue predominantly consists of hepatocytes, which carry out metabolic functions and are responsible for bile production, and biliary cells or cholangiocytes, which line biliary ducts through which bile flows to the digestive tract. These two cell populations originate from common precursors called hepatoblasts. In mice, hepatocyte and biliary lineages segregate at embryonic stage E13. This process is controlled by a network of transcription factors. Biliary cells differentiate around branches of the portal vein and constitute a ring of cells, the ductal plate, where biliary duct formation is initiated. In order to characterize the transcriptional control network involved in biliary duct development, we have first identified new markers of biliary development, namely SOX9 and osteopontin. Using these new markers, we were able to uncover that biliary duct development occurs via an undescribed mode of tubulogenesis, duringwhich transient, primitive ductal structures are formed from the ductal plate. These transient structures are asymmetrical, that is they are lined by biliary cells on their portal side while they are lined by hepatoblasts on their parenchymal side. Maturation of these structures takes place by differentiation of hepatoblasts toward biliary cells, resulting in a radial symmetry of the biliary ducts which become entirely lined by cholangiocytes. In addition, we have revealed an early expression of two members of the transcription factor family Sry-related HMG box (SOX), namely SOX4 and SOX9, in biliary cells. The role of both genes was investigated by means of an in vivo knockout approach. This showed that SOX4 and SOX9 stimulate biliary duct morphogenesis and differentiation. In conclusion, our observations lead to a better understanding of the morphogenesis and of the transcriptional mechanisms which control the differentiation of hepatoblasts into biliary cells Our work offeris new perspectives for diagnosis and understanding human biliary duct malformations.Le foie est majoritairement constitué d’hépatocytes, qui exercent les fonctions métaboliques de l'organe et sécrètent la bile, et de cellules biliaires, ou cholangiocytes, qui bordent les canaux biliaires au travers desquels la bile est drainée vers le tube digestif. Ces deux populations de cellules sont issues de précurseurs communs, appelés hépatoblastes. Chez la souris, la ségrégation des lignées hépatocytaire et biliaire s’opère vers le jour embryonnaire E13 et est contrôlée par un réseau de facteurs de transcription. Les cellules biliaires se différencient autour des branches de la veine porte et constituent un anneau de cellules, appelé plaque ductale, à partir duquel se forment les canaux biliaires. En vue de caractériser le réseau de régulation transcriptionnelle opérant au cours du développement des canaux biliaires, nous avons dans un premier temps identifié de nouveaux marqueurs de développement biliaire, à savoir SOX9 et l'ostéopontine. A l'aide de ces marqueurs, nous proposons un nouveau modèle de tubulogenèse des canaux biliaires qui est caractérisée par la formation transitoire de structures ductales primitives à partir de la plaque ductale. Ces structures transitoires sont asymétriques, c'est-à-dire délimitées du côté portal par des cellules biliaires et du côté parenchymateux par des hépatoblastes. Leur maturation se fait par différenciation des hépatoblastes en cellules biliaires, conférant ainsi une symétrie radiaire aux canaux biliaires qui, à l'état mature, sont entièrement délimités par des cholangiocytes. Nous avons également découvert que deux membres de la famille des facteurs de transcription Sry-related HMG box (SOX), SOX4 et SOX9 sont exprimés dans les cellules biliaires dès le début du développement biliaire. Le rôle de ces deux gènes a été étudié principalement au moyen d'une approche expérimentale in vivo de perte-de-fonction, et nous montrons que SOX4 et SOX9 stimulent la différenciation et la morphogenèse des canaux biliaires. Ces données nous permettent de mieux comprendre les mécanismes transcriptionnels régulant la différenciation des hépatoblastes en cellules biliaires et offrent de nouvelles perspectives dans la compréhension des mécanismes qui peuvent mener aux malformations des voies biliaires chez l’Homme.(SBIM 3) -- UCL, 201

Biliary differentiation and bile duct morphogenesis in development and disease.

The biliary tract consists of a network of intrahepatic and extrahepatic ducts that collect and drain the bile produced by hepatocytes to the gut. The bile ducts are lined by cholangiocytes, a specialized epithelial cell type that has a dual origin. Intrahepatic cholangiocytes derive from the liver precursor cells, whereas extrahepatic cholangiocytes are generated directly from the endoderm. In this review we discuss the mechanisms of cholangiocyte differentiation and bile duct morphogenesis, and describe how developing ducts interact with the hepatic artery. We also present an overview of the mechanisms of biliary dysgenesis in humans.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

Role of the Sox transcription factors in biliary development

info:eu-repo/semantics/nonPublishe

Transcriptional regulation of bile duct morphogenesis

info:eu-repo/semantics/nonPublishe

Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts

In developing liver, cholangiocytes derive from the hepatoblasts and organize to form the bile ducts. Earlier work has shown that the SRY-related High Mobility Group box transcription factor 9 (SOX9) is transiently required for bile duct development, raising the question of the potential involvement of other SOX family members in biliary morphogenesis. Here we identify SOX4 as a new regulator of cholangiocyte development. Liver-specific inactivation of SOX4, combined or not with inactivation of SOX9, affects cholangiocyte differentiation, apico-basal polarity and bile duct formation. Both factors cooperate to control the expression of mediators of the Transforming Growth Factor-β, Notch, and Hippo-Yap signaling pathways, which are required for normal development of the bile ducts. In addition, SOX4 and SOX9 control formation of primary cilia, which are known signaling regulators. The two factors also stimulate secretion of laminin α5, an extracellular matrix component promoting bile duct maturation. We conclude that SOX4 is a new regulator of liver development and that it exerts a pleiotropic control on bile duct development in cooperation with SOX9

Evi1 has conserved restricted expression profile in vertebrate embryos and regulates pronephros development in Xenopus.

info:eu-repo/semantics/publishe

Contrôle du développement des canaux biliaires par la voie de signalisation TGF-beta et le facteur de transcription Sox9

info:eu-repo/semantics/nonPublishe

Evi1 plays an essential role in distal tubule and duct formation in the Xenopus pronephros.

info:eu-repo/semantics/publishe

Notch signaling controls liver development by regulating biliary differentiation

In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate. Notch signals are also required for bile duct morphogenesis, and activation of Notch signaling in the hepatic lobule promotes ectopic biliary differentiation and tubule formation in a dose-dependent manner. Remarkably, activation of Notch signaling in postnatal hepatocytes causes them to adopt a biliary fate through a process of reprogramming that recapitulates normal bile duct development. These results reconcile previous conflicting reports about the role of Notch during liver development and suggest that Notch acts by coordinating biliary differentiation and morphogenesis