Kailynn MacGillivray has earned the Dr Christine Hone-Buske Award for her outstanding publication “Widespread association of Polycomb complex–deposited histone H2A monoubiquitylation with enhancers and neuronal gene regulation”. This research in Science Advances reveals the role of protein modifications in the developing nervous system of the worm C. elegans.
MacGillivray’s work in the Saltzman lab focused on ‘epigenetic’ changes promoted by the protein complexes PRC1 and PRC2. These changes act on histone proteins bound to DNA, serving to turn genes off by packaging them tightly or turn them on by opening up the DNA surrounding the gene.
MacGillivray focused on ubiquitin and methyl molecules attached to histones. “We observed what we thought was a pretty unique phenotype in the worms if you look at PRC1 mutants for C. elegans versus PRC2 mutants.” MacGillivray explains.
“We found that genome-wide these histone modifications weren’t working together in the same way as in mammals or fruit flies. Overall methyl patterns were unexpectedly maintained when ubiquitin was depleted.”
Given this unusual observation, MacGillivray used genome analysis to reveal that genes misregulated in ubiquitin-deficient mutants are enriched for nervous system functions including neuronal differentiation and axon guidance.
An exciting insight from this analysis was that epigenetic changes in PRC1 mutants were enriched at ‘enhancer’ regions: sequences outside of genes that regulate where and when a gene is expressed, even at a distance.
MacGillivray was puzzled: “We had this enrichment at enhancer regions and at neuronal genes, but we didn’t have an obvious link in terms of a gene regulatory standpoint how these two are related in the developing worm. Then we were looking through recent papers and saw a set of enhancers that become nicely accessible or potentially active within neuronal tissue.”
“I found that ubiquitination was most highly enriched at these enhancers compared to enhancers that are accessible in other tissues,” MacGillivray explains. “That was definitely the ‘oh, this makes sense!’ moment that tied this paper together.”
There was excitement in the Saltzman lab as MacGillivray showed the results to her colleagues and mentor. Their animated discussions postulated that epigenetic changes drive temporal control as the nervous system develops and this may be what is constraining activity.
The unique aspects of worm neuronal development can provide insights into other organisms. Some neurodevelopmental dysfunctions in humans are linked the PRC1 complex, and the Saltzman lab is collaborating with researchers in Miami to see if worms provide a model for understanding these changes in humans.
“It’s been great to follow all these different pieces of evidence,” says MacGillivray. “I’ve always been curious, and making these discoveries to me is the whole point of science. I’m glad to have this enthusiasm rewarded with the Dr Christine Hone-Buske Award.”
Congratulations, Kailynn!