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Another Mode of Gene Silencing

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  • Title: Assistant Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute
  • Education: PhD, University of California, Davis, 2001
  • Recommended by: John Rossi

Making an important discovery while still considered young is great, but not necessarily in a funding climate that isn't laying grant money at your feet for follow-up studies. This situation could describe that of Kevin Morris, who was first author on a paper describing transcriptional gene silencing for the first time in 2004, while he was still a postdoc in David Looney's lab at UCSD. Today, Morris is an associate professor at Scripps and his work is focused around elucidating the function of that mechanism.

Transcriptional gene silencing, or TGS, differs from the more well known post-transcriptional gene silencing in that noncoding RNAs turn off transcription by interacting with a gene's promoter. In his study, Morris introduced siRNA into the nucleus of cultured human cells and found that silencing worked through an "epigenetic mode" where the nucleosome was altered structurally, preventing RNA polymerase from binding and transcription from beginning. Instead of having transient silencing, though, TGS can affect cells for a longer time — a month instead of three or four days, which is common to post-transcriptional silencing — opening up the possibility for more effective therapeutic gene knockdown.

"What happens is you get this sort of remodeling that occurs at the gene promoter," Morris says. "If you were considering water and snow and rainfall, [TGS is] stopping the rain from actually falling, whereas post-transcriptional silencing is stopping the water from reaching the ocean by building a dam."

At Scripps, Morris, along with his two graduate students, continues to work on studying TGS. He wants to know exactly how endogenous noncoding RNA can induce the effect and how it can be therapeutically targeted to genes involved in HIV and cancer. He's also partnered with Roche to study how noncoding RNAs are involved in stem cell differentiation, and whether or not TGS can be used to revert cells to a pluripotent state. "The technology doesn't exist right now for looking at noncoding RNAs in this sense," he says, noting that high-throughput sequencing could work. Roche is working on generating an array-based platform to study this.

Going into his PhD, Morris wanted to work on HIV. As a postdoc at UCSD, he worked at the Center for AIDS Research on genetic-based therapy, and during the course of his studies, his curiosity about RNAi got the better of him. He designed a project separate from what he was working on because he thought it'd be "interesting to see if we can just target a promoter and turn it off." Subsequent post-graduate studies with John Rossi allowed him even more time to figure out how TGS was working.

Looking ahead

Morris would like to see better ways to knock down genes in human cells. Right now, he relies on a combination of biotin-labeled oligos or siRNAs, pulldowns, chip assays, and "tweak[ing] protocols that are out there to fit to what we need." If he could invent a technology, it'd be a "promoter array that could measure directionality of transcription." This, he says, would allow him to distinguish the role of bidirectional transcription in gene regulation, cancer development, and HIV infection.

Separate from transcription factors and miRNAs, noncoding RNAs have just begun to make their mark in the area of gene regulation, and Morris hopes that in five years people will be paying more attention to them in this context. "There's a lot more RNA modes of regulation that we're just now starting to see, and it's really going to be fascinating, in my opinion, in the near future," he says.

And the Nobel goes to …

As for the Nobel prize, Morris says he "would probably go the route of Jean Paul Sartre and decline to take that."

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