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Contenuto archiviato il 2024-05-30

The origin and functional evolution of long non-coding RNAs

Final Report Summary - EVOLNCRNAS (The origin and functional evolution of long non-coding RNAs)

The aim of this fellowship was to study the evolution of long non-coding RNAs (lncRNAs) and to evaluate their roles in the specification of mammalian phenotypes. lncRNAs are a class of genes involved in a variety of cellular functions that critically, do not code for proteins. Although there is a growing list of lncRNAs that have been studied to great detail, overall this is a class of genes that is poorly understood. This fellowship aimed at providing critical insights into three aspects of the biology of lncRNAs: 1) understand how lncRNAs are created, 2) identify some of the functions played by lncRNAs; and 3) identify lncRNAs that have contributed to the emergence of mammalian-specific traits.

We sought to understand the evolution and phenotypic impact of lncRNAs by investigate their expression throughout mammalian development. In order to achieve this goal we created a large-scale transcriptomics resource that covers, with unprecedented detail, development for the major mammalian lineages (and a bird). We generated expression profiles throughout development for both males and females for 7 species (human, rhesus macaque, mouse, rat, rabbit, gray short-tailed opossum and chicken) and for 9 major organs (brain, cerebellum, liver, heart, kidney, ovary, testis, placenta and decidua). We started sampling expression profiles as soon as the organs primordiums could be identified (e.g. 4 weeks gestation in humans and embryonic day 10.5 in mouse) all the way through adulthood (including senescence for the two primate species, human and rhesus). This translated into sampling an average of 16 developmental time points per species, for a total of ~ 2,500 RNA-seq libraries. This dataset provides a unique portrait of gene expression throughout mammalian development. We are currently in the process of submitting the complete dataset to a public database (ArrayExpress from EMBL-EBI), where it will be available to the scientific community (and the general public). We anticipate that this will be an invaluable resource for evolutionary and developmental studies and also for biomedical research. We note that our human developmental dataset covers all major developmental milestones (expression profiles were generated for 24 time points throughout development, including 13 pre-natal time-points spanning 4 to 20 weeks post conception) for the major organs and offer a unique portrait of normal human development.

Using these extensive developmental dataset we identified the set of lncRNAs that are expressed throughout development, including those that are developmentally regulated. We identified the major types of regulation of lncRNAs and contrasted to those of known regulators (such as transcription factors). By comparing the expression of lncRNAs with those of protein-coding genes with known functions we were able to predict the most likely functions associated with a large fraction of lncRNAs involved in development. Finally, we identified candidate lncRNAs that together with protein-coding genes underlie phenotypic differences between mammalian species. By studying lncRNAs within a developmental framework we were able to elucidate the potential functions of a large fraction of these genes and cement their position as important regulators and contributors to mammalian phenotypes. These results will be made available in detail in two major publications being currently prepared.

We also extended our work studying lncRNAs expressed in the developing placentas of the 6 mammalian species to human biomedical research by studying lncRNAs in a set of 30 human placentas and associating their expression with different placenta morphologies and pregnancy outcomes. This study is part of a collaboration with Prof. Julie Baker from Stanford University. The results from this work will be available soon as a peer-review publication.

Another important goal of this fellowship was the establishment of collaborations between the host group and the country of origin (U.S.A.). This goal has been met by the establishment of a long-term collaboration with the group of Prof. Julie Baker, a placenta development specialist, from Stanford University. In addition, we have established collaborations with two other groups from the United Sates, the group of Prof. Mike Soares from the University of Kansas (rat development and placenta development), and the group of Prof. John L. VandeBerg from the Texas Biomedical Research Institute (opossum development). We have also established collaborations with groups in Europe and Asia: Dr. Miguel Carneiro from Oporto University (rabbit evolution and development), Prof. Per Jensen from from Likoping University (bird development and evolution) and Prof. Philipp Khaitovich from Skoltech/ShanghaiTech University (human and macaque evolution).