IS THE PLEIOTROPIC FUNCTION OF ENHANCERS EVOLUTIONARILY CONSERVED?

AILÉN ALTAMIRANO; IGNACIO MAYANSKY; IAN LAIKER; NICOLAS FRANKEL

Taller; V Taller de Biología Celular y del Desarrollo; 2022

Transcriptional enhancers determine when and where a gene is expressed. Historically, enhancers havebeen characterized as elements that drive gene expression in a single spatio-temporal context.However, in the last years, several studies have shown that many enhancers can act in multipledevelopmental contexts, thus being pleiotropic. Although we know that a considerable number ofenhancers in animal genomes are pleiotropic, we are unaware of the evolutionary forces that act onpleiotropic enhancers. The aim of our work is to determine whether the pleiotropic function ofenhancers is evolutionarily conserved in distant species. The conservation of the pleiotropic function ofenhancers may indicate that pleiotropy is maintained by selection. Previous analyses from our labRESÚMENESdemonstrated that the pleiotropic activity of enhancers of the shavenbaby gene is conserved betweenD. melanogaster and D. virilis, two species that diverged ~40 MYA. Bearing this in mind, we wonderedwhether the function of pleiotropic enhancers genome-wide would be conserved between these twospecies. In order to explore this idea, we first categorized D. melanogaster enhancers as contextspecificor pleiotropic by using chromatin structure data across developmental contexts. Subsequently,we searched for enhancer orthologs in D. virilis employing two different methods: an alignment-basedmethod (reciprocal LiftOver) and an “alignment-free” method that we conceived, which considers theco-occurrence of k-mers in a limited search space. Using these methods, we found orthologs for ~90%of D. melanogaster enhancers. Our next goal is to study the activity of orthologous enhancers in D.virilis through the analysis of chromatin structure in multiple developmental contexts. This analysis willallow us to uncover the extent of conservation in the function of pleiotropic enhancers genome-widebetween D. melanogaster and D. virilis and to comprehend the relevance of pleiotropy withinregulatory DNA.