Matthew Thomas Holt

Presented by Tom Muir
B.S., Western Washington University
Identification of a Functional Hotspot on Ubiquitin Required
for Stimulation of Methyltransferase Activity on Chromatin

Matt Holt hails from Seattle and, like many from that part of the world, was lured to New York by the promise of better coffee and a more diverse climate. Having majored jointly in biochemistry and chemistry, Matt found his way to my lab where he became interested in how a molecular “kiss of death” could be redeployed as an “embrace of life.” More specifically, Matt became interested in how protein ubiquitylation (a modification more associated with destruction) helps positively regulate transcriptional outputs in the context of chromatin.

Previously my lab, working with colleagues here at Rockefeller, had shown that ubiquitylation of histone 2B directly stimulates key methyltransferase enzymes involved in transcription initiation and elongation. But how does ubiquitin do this? This is what drove Matt’s thesis research. Matt’s approach was to systematically tinker with the system in the hope of finding its essence — basically a structure-activity analysis on chromatin. Doing such a thing was but a pipe dream when Matt started — our approach to manufacturing the ubiquitylated chromatin was precise, but highly artisanal, and it would have taken decades to make all the molecules Matt needed to rigorously perform the analysis. Faster methods were needed.

Solving this synthetic chemistry problem was at the heart of Matt’s thesis work, and solve it he did, by developing ingenious approaches that allowed him to systematically mutate the entire ubiquitin protein surface in the context of a chromatin template. From this analysis Matt concluded, quite shockingly I think, that only a tiny portion of the ubiquitin surface is needed to stimulate the methyltransferases — he discovered the key “functional hotspot” on the protein. Moreover, he found that a different hotspot on ubiquitin is needed for other aspects of ubiquitin activity on chromatin. Thus, we have come to think of ubiquitin as an information rich histone modification, able to orchestrate different outputs, probably simultaneously, from the same locale. All in all, Matt accomplished an impressive body of work during his time at Rockefeller. His methodical and careful approach to science has paid off handsomely.

Matt was equally systematic in his explorations of the New York nightlife. Indeed, he discovered several additional “hotspots” during his explorations of downtown Manhattan. These included the amazing Mars Bar in the East Village — certainly the greatest dive bar in the western hemisphere. The recent demolition of the bar was barely even noticed by the regulars, but was widely viewed as the end of an era in the city.

Matt’s graduation sees the end of an era in my lab, as he was the last student in my group actually working at Rockefeller, with Tarun Kapoor’s help. But as a chapter ends for me, a new one opens for him, and so I wish him all success in the future.