Sebé-Pedrós group
Comparative regulatory genomics
Intro
A fundamental question in biology is how the diverse cell types are encoded by a single genome. However, the diversity and evolution of cell type identity programs remain largely unexplored beyond selected tissues in a few species.
Similarly, little is known about the emergence of genome regulatory mechanisms that support cell type differentiation programs and long-term cellular memory, such as genome spatial compartmentalization and repressive chromatin states. What are the regulatory innovations linked to the origin of stable cell differentiation? How do cell identity gene regulatory networks evolve? And how do these genetic changes translate into cellular novelties?
To address these and related questions, we combine high-throughput chromatin profiling and single-cell genomics technologies with advanced computational methods. This allows us to characterize and compare cell type programs and genome regulatory architectures in phylogenetically diverse systems.
The Biodiversity Cell Atlas: towards a cell type tree of life
Cells are the fundamental units of life – underlying cooperative functions in multicellular organisms and complex temporal life cycles in microbial eukaryotes. Recent advances in single-cell genomics technologies, along with the growing availability of chromosome-scale genome sequences, have opened the door to systematically mapping cell types across a wide range of organisms.
The goal of the Biodiversity Cell Atlas (BCA) is to foster a community effort to construct whole-organism cell atlases across the diversity of life. This initiative aims to work in a phylogenetically informed manner, supported by high-quality genomes, and employ shared standards that facilitate cross-species comparisons. This coordinated effort will enhance our understanding of life’s evolution and diversity at the cellular level: from gene regulatory programs and cell type molecular profiles to biological interactions between species.
In my Associate Faculty position at Sanger within the Tree of Life Programme, my primary goal will be to contribute my expertise in non-model organism single-cell genomics to generate data for the Biodiversity Cell Atlas. This work will build on the Darwin Tree of Life (DToL) project, leveraging the high-quality DToL genomes. In turn, molecular cell atlases will improve our understanding of genome organization, regulation, and function. The project will also involve strong collaboration with Cellular Genetics and Scientific Operations to ensure the scalability of this phylogenetic single-cell sampling effort.
Biodiversity epigenomics: understanding the evolution of genome regulatory mechanisms
Access to eukaryotic genetic information is controlled by a complex nucleoproteic interface known as chromatin. The evolution of chromatin represents a radical shift in genome function: transitioning from a largely accessible prokaryotic genome to a repressive ground state in eukaryotes, with restricted access to genetic information. The main components of eukaryotic chromatin include histone proteins and their associated chaperones, remodellers, and readers/writers/erasers of histone post-translational modifications (hPTMs). Additionally, sequence-specific transcription factors (TFs) and proteins that mediate chromatin folding (e.g., CTCF and cohesins) play crucial roles. Collectively, these chromatin processes are essential for the establishment and maintenance of cell identities, whether stable cell types or temporal cellular states.
We have a long-standing interest in the evolution of transcription factors and other chromatin components, such as histone modifiers and readers. Similarly, we employ comparative proteomics to explore the diversity of hPTMs across species and to characterize the molecular players involved in hPTM readout. We also investigate the evolution of genome regulation through chromatin folding and compartmentalization.
Understanding of genome regulation from a phylogenetic perspective will not only reveal how these mechanisms evolved, but also identify shared, fundamental principles of eukaryotic genome function.
