Periodic Reporting for period 1 - eXcape3D (Functional dissection of X-linked regulatory DNA: unravelling the impact of genome topology on transcriptional regulation)
Período documentado: 2019-04-01 hasta 2021-03-31
The “eXcape3D” project was designed to understand how the genome looks and works by using X Chromosome Inactivation (XCI) as a model system. XCI ensures proper X-linked gene dosage between females (XX) and males (XY), is essential for female development, and results in the transcriptional silencing of almost one entire X chromosome in all cells of every female mammals, including women. Intriguingly, a subset of X-linked genes, the ‘escapees’, resist XCI and remain expressed from both the active (Xa) and inactive (Xi) X chromosomes within the same nucleus. XCI escape is highly relevant for female development and sexual dimorphism. Women born with a single X (XO) are affected by Turner syndrome, but the majority of human XO embryos die in utero. XX women are more susceptible than XY men to autoimmune diseases and this is thought to be due to an excess dose of immunity-related X-linked genes that are prone to be reactivated along the Xi.
How escapees resist XCI remains a mystery. According to previous work, the 3D organization of these active loci might be important for their expression. However, whether the structural features of escapees are cause or consequence of their activity is hard to conclude.
The objectives of this MSCA project have been to (a) identify DNA regulatory elements that drive escape from XCI, and (b) determine the exact causal relationship between transcriptional activity and chromosome architecture in the context of Xi. The project also aimed to nurture the development of the Fellow into a highly-qualified expert scientist who is fully prepared and motivated to continue her career as a junior group leader in the European Research Area.
How escapees resist XCI remains a mystery. According to previous work, the 3D organization of these active loci might be important for their expression. However, whether the structural features of escapees are cause or consequence of their activity is hard to conclude.
The objectives of this MSCA project have been to (a) identify DNA regulatory elements that drive escape from XCI, and (b) determine the exact causal relationship between transcriptional activity and chromosome architecture in the context of Xi. The project also aimed to nurture the development of the Fellow into a highly-qualified expert scientist who is fully prepared and motivated to continue her career as a junior group leader in the European Research Area.
The obtained results are highly relevant for the Dosage Compensation and Epigenetics fields, providing novel and unexpected insights into the regulation of escape from XCI. The project revealed that genes escaping XCI constitutively (i.e. in all tissues and all individuals) or facultatively (i.e. in a tissue- and/or individual-specific manner) are characterized by different epigenetic features. Such features, including 3D topology, are likely to underlie different strategies set-up by different X-linked genes to resist XCI during early development and/or in different context throughout the lifespan of female mammals. Furthermore, the results obtained in this project led to novel exciting questions that the Fellow is ready to explore in her own line of research as a fully independent scientist.
During the MSCA, the Fellow reinforced her expertise in molecular biology and acquired a multitude of new skills, including computational skills for the bioinformatic analysis of (epi)genomic data. The Fellow learned how to plan and monitor an interdisciplinary project, she supervised Master and PhD students, followed a tailored-design mentoring and coaching program for the next generation of leaders, and effectively transferred her knowledge by sharing the protocols and tools that she developed with younger students and peers.
The results stemming from this project were broadly disseminated within and outside EMBL, at several international conferences and workshops. Disseminating her finding significantly enhanced the Fellow’s network and allowed her to reinforce critical knowledge exchange by establishing new collaborations with scientists spread across Europe, from Germany to Italy, Sweden, France, and Spain. The Fellow reached a broad audience of researchers within the Molecular Biology, Epigenetics, and Dosage Compensation fields by writing two comprehensive reviews focusing on X-inactivation and the interplay between genome topology and function. She also wrote one technical manuscript describing an effective method to explore the 3D organization of the genome at very high resolution, and she is currently preparing the manuscript describing her main research results.
The Fellow also took part into several outreach activities. As project manager for the Italian community in Heidelberg, she reinforced her collaboration with Native Scientist, a non-profit organization that promotes cultural and linguistic diversity in STEM. The Fellow established a network of >30 scientists and organized two workshops in primary schools of the Heidelberg area. She also contributed to AIRI-CLIP, an initiative promoted by the Italian Association of Researchers that was launched during the COVID-19 pandemic to provide summaries of relevant scientific publications translated in Italian to inform the general public. She contributed to the “EMBL-Nigeria pen pals project”, a program that aims to inspire the next generation of scientists, and also shared her results and experiences as a immigrant scientist in the frame of the ‘EMBL School Ambassador’ program. Finally, the Fellow participate to the online talk series “Women in Science” organized by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst – DAAD), where she answered questions of young students looking for opportunities to leave their countries to pursue their Master and/or PhD studies abroad.
During the MSCA, the Fellow reinforced her expertise in molecular biology and acquired a multitude of new skills, including computational skills for the bioinformatic analysis of (epi)genomic data. The Fellow learned how to plan and monitor an interdisciplinary project, she supervised Master and PhD students, followed a tailored-design mentoring and coaching program for the next generation of leaders, and effectively transferred her knowledge by sharing the protocols and tools that she developed with younger students and peers.
The results stemming from this project were broadly disseminated within and outside EMBL, at several international conferences and workshops. Disseminating her finding significantly enhanced the Fellow’s network and allowed her to reinforce critical knowledge exchange by establishing new collaborations with scientists spread across Europe, from Germany to Italy, Sweden, France, and Spain. The Fellow reached a broad audience of researchers within the Molecular Biology, Epigenetics, and Dosage Compensation fields by writing two comprehensive reviews focusing on X-inactivation and the interplay between genome topology and function. She also wrote one technical manuscript describing an effective method to explore the 3D organization of the genome at very high resolution, and she is currently preparing the manuscript describing her main research results.
The Fellow also took part into several outreach activities. As project manager for the Italian community in Heidelberg, she reinforced her collaboration with Native Scientist, a non-profit organization that promotes cultural and linguistic diversity in STEM. The Fellow established a network of >30 scientists and organized two workshops in primary schools of the Heidelberg area. She also contributed to AIRI-CLIP, an initiative promoted by the Italian Association of Researchers that was launched during the COVID-19 pandemic to provide summaries of relevant scientific publications translated in Italian to inform the general public. She contributed to the “EMBL-Nigeria pen pals project”, a program that aims to inspire the next generation of scientists, and also shared her results and experiences as a immigrant scientist in the frame of the ‘EMBL School Ambassador’ program. Finally, the Fellow participate to the online talk series “Women in Science” organized by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst – DAAD), where she answered questions of young students looking for opportunities to leave their countries to pursue their Master and/or PhD studies abroad.
The obtained results are timely and target a broad audience. The interest in understanding how X-dosage contributes to sexual dimorphism and disease predisposition has very rapidly increased, allowing the Fellow to establish new interdisciplinary collaborations in the field of autoimmunity.
In the frame of this project the Fellow developed a novel epigenetic tool to induce the targeted and controlled formation of heterochromatin. This innovative tool has the potential to be applied to several CRISPR-Cas9 high-throughput technologies to study the interplay between genotype and phenotype, and is very likely to become extensively used by the research community.
During the MSCA the Fellow was awarded the L’Oréal-UNESCO Fellowship for Women in Science, which aims to facilitate the progress of highly qualified young women whose scientific careers are threatened by the difficulties of balancing science and family life. The Fellow was also selected for the first EMBL Leadership and Excellence for Aspiring Postdocs (LEAP) program, an innovative coaching programme designed to enable women postdocs to challenge themselves and their environment as they strive for their next career step as group leaders. Receiving these awards not only enriched the scientific network of the Fellow but also gave her the opportunity to take part into policy-changing discussions aiming to improve the number of women reaching leading position in STEM. For example, the Fellow contributed to the round table “On the way to the top: female careers at universities and research institutions” which took place in the contest of the conference “Impetus for Europe – equality-oriented structures and diversity in research” organized by the German Federal Ministry of Education and Research.
In the frame of this project the Fellow developed a novel epigenetic tool to induce the targeted and controlled formation of heterochromatin. This innovative tool has the potential to be applied to several CRISPR-Cas9 high-throughput technologies to study the interplay between genotype and phenotype, and is very likely to become extensively used by the research community.
During the MSCA the Fellow was awarded the L’Oréal-UNESCO Fellowship for Women in Science, which aims to facilitate the progress of highly qualified young women whose scientific careers are threatened by the difficulties of balancing science and family life. The Fellow was also selected for the first EMBL Leadership and Excellence for Aspiring Postdocs (LEAP) program, an innovative coaching programme designed to enable women postdocs to challenge themselves and their environment as they strive for their next career step as group leaders. Receiving these awards not only enriched the scientific network of the Fellow but also gave her the opportunity to take part into policy-changing discussions aiming to improve the number of women reaching leading position in STEM. For example, the Fellow contributed to the round table “On the way to the top: female careers at universities and research institutions” which took place in the contest of the conference “Impetus for Europe – equality-oriented structures and diversity in research” organized by the German Federal Ministry of Education and Research.