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Opening the 'Black Box' of Chromatin

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  • Title: Assistant Professor, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School
  • Education: MD/PhD, Stanford University, 2002
  • Recommended by: Phillip Zamore

After years of studying transcription in other people's labs, Oliver Rando, now at the University of Massachusetts Medical School, is finally leading a lab of his own focusing on the genome-wide structure and function of a key regulator, chromatin.

Rando studies everything from the sequence of repeating histones to nucleosome positioning, covalent modifications, and the histone variants themselves. "We're interested in how DNA is packaged in the cell — in other words, what chromatin structure looks like," he says. "We're interested in that both independently as well as a potential carrier for epigenetic information." He runs a broad array of tools, spanning homemade and commercial microarrays to deep sequencing, to make sense of this information.

Over the past several years, Rando has focused on mapping chromatin structure in yeast, and how that changes as a cell proceeds through its cycle. "All of these basic mechanistic questions about how nucleosomes move and interact with each other after replication have huge consequences for how and whether you can inherit chromatin states," he says. He notes that while a majority of people believe chromatin states to be heritable, he contends that there's no hard proof yet. "Whether chromatin states are heritable is, to my mind, still an open question."

Since his undergrad days, Rando has always worked in transcription labs, and it was from these early experiences that he noticed how little people knew about what was regulating the process of transcription. "It became very clear over my early years of training that chromatin was a fairly mysterious black box and often people in the transcription field would invoke chromatin when they didn't understand something," he says. While at Jerry Crabtree's Stanford lab, Rando did his PhD on the chromatin remodeling complex, which converts the energy released during ATP hydrolysis to remodel nucleosome structure. "We realized that there was no way to find lots of nucleosomes at once, and that's what led me to start working on how to do these mapping things on a genomic scale."

Looking ahead

A big technical challenge is describing the next level of chromatin structure, Rando says. "Characterization of beads on a string is, at this point, mature. We can find nucleosomes. The folding of beads on a string — the next level of compaction — is called 30-nanometer fiber, and at this point, no one has any hint for how to think about mapping at 30-nanometer fiber. But I think it will be tremendously illuminating to do so," he says.

In the immediate future, Rando thinks the community will move toward mapping chromatin states. "How do nucleosomes move when you turn on a gene, or, in our case, during genomic replication?"

Publications of note

A lingering question in Rando's mind is why there are so many histone modifications. In a paper published in PLoS Biology in 2005, he and his team used a high-resolution tiling array to look at the occurrence of combinations of 12 histone modifications across thousands of nucleosomes in growing S. cerevisiae. They found that two groups of co-occurring modifications could distinguish nucleosomes at one location from another. Rando expects this to become more of a focus in the coming years.

And the Nobel goes to …

Asked what he'd like to win the Nobel for, Rando says his eye isn't on the prize. "I distrust people whose goal in science is to win prizes." When pressed, he says, "I suppose it would be for discovering an epigenetic therapy that cured a huge number of cancers."

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