Interrelations entre le récepteur alpha des œstrogènes et le récepteur nucléaire coup-tfi dans le contrôle de la prolifération et de la différenciation de cellules mammaires

Les œstrogènes (E2) sont connues pour leurs rôles dans la croissance des tumeurs mammaires. Ces hormones exercent leurs effets par l intermédiaire de récepteurs spécifiques, les récepteurs des œstrogènes, ERa et ERb. Les ER appartiennent à la superfamille des récepteurs nucléaires qui portent un domaine de liaison du ligand, un domaine d interaction avec l ADN et des fonctions de transactivation (AF-1 et AF-2) leur permettant d agir comme des facteurs de transcription inductibles. Les récepteurs nucléaires orphelins COUP-TFI sont susceptibles de moduler l activité du ERa. Afin d appréhender l impact des interrelations entre ERa et COUP-TFI au sein des cellules mammaires, nous avons établi des clones de cellules mammaires sur-exprimant stablement COUP-TFI. L analyse de ces clones montre que COUP-TFI favorise la prolifération et stimule les capacités de migration de cellules ERa positives. COUP-TFI module sélectivement l expression de gènes E2-régulés endogènes et exerce en particulier une stimulation de la fonction de transactivation AF-1 du ERa.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Signaling by steroid hormones in the 3D nuclear space

Initial studies showed that ligand-activated hormone receptors act by binding to the proximal promoters of individual target genes. Genome-wide studies have now revealed that regulation of transcription by steroid hormones mainly depends on binding of the receptors to distal regulatory elements. Those distal elements, either enhancers or silencers, act on the regulation of target genes by chromatin looping to the gene promoters. In the nucleus, this level of chromatin folding is integrated within dynamic higher orders of genome structures, which are organized in a non-random fashion. Terminally differentiated cells exhibit a tissue-specific three-dimensional (3D) organization of the genome that favors or restrains the activity of transcription factors and modulates the function of steroid hormone receptors, which are transiently activated upon hormone exposure. Conversely, integration of the hormones signal may require modifications of the 3D organization to allow appropriate transcriptional outcomes. In this review, we summarize the main levels of organization of the genome, review how they can modulate the response to steroids in a cell specific manner and discuss the role of receptors in shaping and rewiring the structure in response to hormone. Taking into account the dynamics of 3D genome organization will contribute to a better understanding of the pleiotropic effects of steroid hormones in normal and cancer cells.We thank all members of the Chromatin and Gene Expression group (CRG, Barcelona) and the members of the 4DGenome project (CRG and CNAG-CRG, Barcelona) for helpful discussions. Research in the Beato’s laboratory receives funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Synergy grant agreement 609989 (4DGenome). The content of this manuscript reflects only the author’s views and the Union is not liable for any use that may be made of the information contained therein. We also acknowledge support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017” and Plan Nacional (SAF2016-75006-P), as well as support of the CERCA Programme/Generalitat de Catalunya

COUP-TFI and estrogen receptor interplay in breast cancer : evidence for in vivo regulation of Cathepsin D

Poste

Involvement of COUP-TFs in Cancer Progression

International audienceThe orphan receptors COUP-TFI and COUP-TFII are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis, as demonstrated by loss-of-function COUP-TFI and/or COUP-TFII mutant mice. Although COUP-TFs are expressed in a wide range of tissues in adults, little is known about their functions at later stages of development or in organism homeostasis. COUP-TFs are expressed in cancer cell lines of various origins and increasing studies suggest they play roles in cell fate determination and, potentially, in cancer progression. Nevertheless, the exact roles of COUP-TFs in these processes remain unclear and even controversial. In this review, we report both in vitro and in vivo data describing known and suspected actions of COUP-TFs that suggest that these factors are involved in modification of the phenotype of cancer cells, notably of epithelial origin

90 YEARS OF PROGESTERONE: Molecular mechanisms of progesterone receptor action on the breast cancer genome

Gene regulation by steroid hormones has been at the forefront in elucidating the intricacies of transcriptional regulation in eukaryotes ever since the discovery by Karlson and Clever that the insect steroid hormone ecdysone induces chromatin puffs in giant chromosomes. After the successful cloning of the hormone receptors toward the end of the past century, detailed mechanistic insight emerged in some model systems, in particular the MMTV provirus. With the arrival of next generation DNA sequencing and the omics techniques, we have gained even further insight into the global cellular response to steroid hormones that in the past decades also extended to the function of the 3D genome topology. More recently, advances in high resolution microcopy, single cell genomics and the new vision of liquid-liquid phase transitions in the context of nuclear space bring us closer than ever to unravelling the logic of gene regulation and its complex integration of global cellular signaling networks. Using the function of progesterone and its cellular receptor in breast cancer cells, we will briefly summarize the history and describe the present extent of our knowledge on how regulatory proteins deal with the chromatin structure to gain access to DNA sequences and interpret the genomic instructions that enable cells to respond selectively to external signals by reshaping their gene regulatory networks.First, the authors thank all the members of the Chromatin and Gene Expression Group, who had performed most of the experiments commented in this review and have made suggestions for the text. The authors also thank their collaborators, most of them cited as authors of the referenced papers. The authors thank the CRG for the continuous support of the group and for the availability of essential core facilities. The experimental work mentioned was supported by the core funding of the CRG, the European Research Council (Project ‘4D Genome’ 609989), the Ministerio de Economía y Competitividad (Project G62426937) and the Generalitat de Catalunya (Project AGAUR SGR 575). We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa as well as CERCA Programme / Generalitat de Catalunya

Signaling by steroid hormones in the 3D nuclear space

Initial studies showed that ligand-activated hormone receptors act by binding to the proximal promoters of individual target genes. Genome-wide studies have now revealed that regulation of transcription by steroid hormones mainly depends on binding of the receptors to distal regulatory elements. Those distal elements, either enhancers or silencers, act on the regulation of target genes by chromatin looping to the gene promoters. In the nucleus, this level of chromatin folding is integrated within dynamic higher orders of genome structures, which are organized in a non-random fashion. Terminally differentiated cells exhibit a tissue-specific three-dimensional (3D) organization of the genome that favors or restrains the activity of transcription factors and modulates the function of steroid hormone receptors, which are transiently activated upon hormone exposure. Conversely, integration of the hormones signal may require modifications of the 3D organization to allow appropriate transcriptional outcomes. In this review, we summarize the main levels of organization of the genome, review how they can modulate the response to steroids in a cell specific manner and discuss the role of receptors in shaping and rewiring the structure in response to hormone. Taking into account the dynamics of 3D genome organization will contribute to a better understanding of the pleiotropic effects of steroid hormones in normal and cancer cells.We thank all members of the Chromatin and Gene Expression group (CRG, Barcelona) and the members of the 4DGenome project (CRG and CNAG-CRG, Barcelona) for helpful discussions. Research in the Beato’s laboratory receives funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Synergy grant agreement 609989 (4DGenome). The content of this manuscript reflects only the author’s views and the Union is not liable for any use that may be made of the information contained therein. We also acknowledge support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017” and Plan Nacional (SAF2016-75006-P), as well as support of the CERCA Programme/Generalitat de Catalunya

3D modeling of chromatin structure: is there a way to integrate and reconcile single cell and population experimental data?

The genome is organized in a hierarchical fashion within the nucleus in interphase. This nonrandom folding of the chromatin fiber is thought to play important roles in the processing of the genetic information. Therefore, a better knowledge of the mechanisms underlying the three-dimensional structure of the genome appears essential to fully understand the nuclear processes including transcription and replication. Fluorescent in situ hybridization (FISH) and molecular biology methods deriving from the Chromosome Conformation Capture technique are the methods of choice to study genome 3D organization at different levels. Although these single cell and population methods allowed to highlight similar chromatin structures, they also show frequent discrepancies which might be better understood by improving the capacity to generate actual 3D models of organization based on the different types of data available. This review aims at giving an overview of the principles, advantages, and limits of microscopy and molecular biology methods of analysis of genome structure and at discussing the different approaches of modeling of chromatin classically used and the improvements that are necessary to reach a better understanding on the links between chromatin structure and its spatial organization.This review has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement 609989. We acknowledge funding from the Spanish Ministry of Economy and Competitiveness (BFU2013-47736-P) and the European Union's Horizon 2020 research and innovation programme under grant agreement No 676556 and support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017’, SEV-2012-0208 and of the CERCA Programme/Generalitat de Catalunya to the CR

How will climate change affect pasture plant species and their reserves?

National audienc

ATP, Mg2+, nuclear phase separation, and genome accessibility

Misregulation of the processes controlling eukaryotic gene expression can result in disease. Gene expression is influenced by the surrounding chromatin; hence the nuclear environment is also of vital importance. Recently, understanding of chromatin hierarchical folding has increased together with the discovery of membrane-less organelles which are distinct, dynamic liquid droplets that merge and expand within the nucleus. These 'sieve'-like regions may compartmentalize and separate functionally distinct regions of chromatin. This article aims to discuss recent studies on nuclear phase within the context of poly(ADP-ribose), ATP, and Mg2+ levels, and we propose a combinatorial complex role for these molecules in phase separation and genome regulation. We also discuss the implications of this process for gene regulation and discuss possible strategies to test this.The experimental work mentioned was supported by the European Research Council (Project 4D Genome 609989), the Ministerio de Economía y Competitividad (project G62426937), and the Generalitat de Catalunya (project Agència de Gestió d'Ajuts Universitaris i de Recerca SGR 575)