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Researchers Report Rapid Enhancer Evolution During Mammalian Radiation

NEW YORK (GenomeWeb) – Enhancer elements have evolved quickly during mammalian radiation and diversification — often from existing ancestral sequences — while functional elements such as promoters have remained relatively conserved, according to a new study in Cell.

An international team led by investigators in the UK used histone H3K4- and H3K27-focused chromatin immunoprecipitation sequencing to examine genome-wide promoter and enhancer patterns in liver samples from 20 species, representing half a dozen mammalian orders.

By looking at a phylogenetically broad swath of mammalian species, including marsupials, the researchers could compare and contrast rates of promoter and enhancer evolution across the mammalian radiation, explained co-senior author Paul Flicek, head of vertebrate genomics at the European Molecular Biology Laboratory-European Bioinformatics Institute.

Whereas liver promoters were largely conserved across the mammalian genomes, he and his co-authors found, enhancer elements were more prone to rapid evolution. And notably, enhancers with the swiftest apparent evolution tended to fall near genes showing signs of positive selection in a given species, pointing to interplay between protein-coding and regulatory adaptations.

"It looks like the regulatory network might be working jointly with the evolution of the genes to produce new functions or new adaptations," co-first author Camille Berthelot, a post-doctoral researcher in Flicek's EMBL-EBI lab, told GenomeWeb. 

Previous studies hint at the potential for swift enhancer shifts over the course of mammalian evolution, leading to species-specific enhancer patterns. On the other hand, other genome comparisons have highlighted the conservation and sequence constraint that can exist across certain vertebrate regulatory sequences.

To tease this apart further, Flicek, Berthelot, and colleagues did ChIP-seq on adult liver tissue from 20 diverse mammalian species, targeting H3K4me3 and H3K27ac — histone marks that coincide with transcription initiation sites (i.e., active promoters) and enhancer elements, respectively.

By quantifying levels of the two histones from their ChIP-seq data, the researchers narrowed in on tens of thousands of genomic sites exhibiting promoter- or enhancer-related histone peaks in liver samples from each of the mammalian species.

They then looked at how these elements tracked over evolutionary time in the mammalian family tree. At one end of the spectrum were regions with high levels of conservation and activity in all the animals. At the other: regulatory elements with low conservation — a collection that's expected to include regulatory elements that have evolved rapidly in a just a subset of the mammalian species.

As it turned out, the transcription initiation/promoter sites were overwhelmingly conserved in the liver samples. In contrast, though, enhancer elements appeared far more apt to undergo rapid evolution — often through tweaks in ancestral sequences that prompted them to take on regulatory roles in some mammals but not others.

"Until we see more tissues, we don't really know the full extent of how evolution has done this," Flicek said. "But it is pretty clear that there is a set of sequences that were present in the ancestor that have been grabbed onto and used as enhancers differently in different species."

"This opens up some interesting questions about regulatory potential in the genome," he noted. "If this is some ancestral sequence that has been successfully adapted in a regulatory role in some species and not in others, does that regulatory potential still exist? Can it be adapted in those other species in the future?"

Through a series of follow-up analyses, the researchers garnered additional clues about the nature of promoter and enhancer evolution over time and their potential relationships with neighboring genes.

For instance, their data revealed especially high conservation for promoter sequence falling near housekeeping genes or genes that are commonly used by all cells, Berthelot noted. In contrast, genes with liver-specific functions were typically associated with the subset of conserved enhancer sites.

Enhancers showing species-specific differences, meanwhile, frequently neighbored genes under positive selection — a relationship that the team examined further in species noted for their unusual adaptations such as the naked mole rat and dolphin.

The researchers have now started scrutinizing regulatory patterns in other tissue types, though Flicek noted that sufficient samples are sometimes tricky to come by for the more exotic species included in the current study. 

The team is also looking at the other types of data that may be gleaned from tissues already on hand such as histone marks associated with poised rather than active enhancers. 

"Some of the other marks do denote poised enhancers — ones that may become active or may have been active in an earlier stage of development," Flicek said. "It certainly would be interesting to see what those look like and to compare the enhancer maps that we have in the liver to maps in other tissues."

Finally, the group is keen to expand its approach to other mammalian species that have sufficiently high-quality genome assemblies, provided suitable tissues are available for such analyses.

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