Deep learning of enhancer codes highlights similarities between mammalian and avian telencephalon cell types [mpra]

Combinations of transcription factors govern the identity of cell types, which is reflected by genomic enhancer codes. We utilized deep learning to characterize these enhancer codes and devised three novel metrics to compare cell types in the telencephalon between mammals and birds. To this end, we generated single-cell multiome and spatially-resolved transcriptomics data of the chicken telencephalon. Enhancer codes of orthologous non-neuronal and GABAergic cell types show a high degree of similarity across vertebrates, while excitatory neurons of the mammalian neocortex and avian pallium exhibit varying degrees of similarity. Enhancer codes of avian mesopallial neurons are most similar to those of mammalian deep layer neurons. With this study, we present generally applicable deep learning approaches to characterize and compare cell types solely based on genomic sequences. Overall design: A saturation mutagenesis library of the FIRE enhancer is cloned in a lentiviral MPRA reporter. Mouse BV2 cells are transduced with the virus and RNA and genomic DNA are harvested after 48 hours. The reporter barcodes are sequenced to estimate enhancer activity of each sequence.