Dr Alvaro Rada Iglesias; Institute of Biomedicine and Biotechnology of Cantabria
Alvaro Rada Iglesias received his M.Sc. in Biology by the University of Leon in 2001, being recognized as the best academic curriculum of that year. Then, he obtained his PhD in 2007 at Uppsala University (Sweden), where he worked in the laboratory of Prof. Claes Wadelius. After a short post-doctoral work in the Linnaeaus Centre for Bioinformatics (Uppsala University, Sweden) under the supervision of Prof. Jan Komorowski, he obtained an EMBO long-term fellowship to continue his postdoctoral career in the laboratory of Prof. Joanna Wysocka at Stanford University (USA), where he stayed between 2009-2013. In 2013, he was recruited by the University of Cologne as a Junior Research Group Leader at the Centre for Molecular Medicine Cologne, where he successfully started his independent research group. This was recognized with an EMBO Young Investigator award (EMBO YIP) in 2017. In July 2018 he was recruited as a Principal Investigator by the University of Cantabria to direct his research group at the Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC). In 2020, he became a Tenured Scientist at the Consejo Superior de Investigaciones Científicas (CSIC). In recent years, his work has been recognized by an EMBO Young Investigator award (EMBO YIP; 2017), the José Luís Gómez Skarmeta award (2020) and an ERC Consolidator grant (2019).
During vertebrate embryogenesis, developmental genes are expressed with remarkable specificity (i.e. expression of the correct genes in the correct cell types) and spatio-temporal precision (i.e. low transcriptional variation within a field of cells). It is widely accepted that the establishment of cell-type specific gene expression programs is largely dependent on the regulatory activity of enhancers. However, the mechanisms that enable enhancers to induce their target genes with the required precision and specificity are still poorly understood. Using a synthetic engineering approach, we recently showed that enhancer-associated CpG islands (CGI) act as tethering elements that increase the physical and functional communication between distal enhancers and their target genes, particularly those with large CGI clusters in their promoters (i.e. developmental genes). Moreover, using single-cell measurements, we also uncovered that CGI contribute to the precise induction of developmental genes by increasing transcriptional burst size and frequency. On the other hand, we noticed that developmental genes tend to be located close to TAD boundaries, while their cognate enhancers have a more random distribution within TADs. Notably, to interrogate whether the positioning of developmental genes within TADs has any functional relevance, we generated various genetic rearrangements in two selected loci (i.e. Gbx2/Asb18; Six3/Six2). Interestingly, these experiments revealed that the presence of CTCF site clusters, and developmental genes close to TAD boundaries synergistically strengthens transcriptional insulation and prevents enhancers from activating non-target genes. Overall, our findings provide novel insights into the mechanisms controlling transcriptional precision and specificity during development, which, in turn, can also help us to understand and predict the long-range pathological effects of human structural variation.
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