Reading the rules of gene regulation with CRISPR

We have barely begun to crack open the rulebook for the vast noncoding regions of the genome. Two new methods, building on CRISPR advances, may help reveal some of the pages. 

We have a reasonable understanding of the rules behind the genome's protein-coding components. We can look at a DNA sequence and point with confidence to where a gene's coding region begins, where it ends, and pieces of its geography.

For the remaining 98 percent of the genome—the part that dictates which genes a cell reads—it's a different story. What knowledge we have of the rules governing this "dark matter" comes from from studying and manipulating individual bits of noncoding DNA one at a time. The rulebook that governs how the noncoding genome works, however, has remained out of reach.

"Ninety percent of the genetic variations that affect human disease are in the noncoding regions," said Broad founding director Eric Lander. "But we haven't had any way to tell, in a systematic way, which regulators affect which genes."

In a pair of newly published Science papers, two research teams at the Broad show how methods leveraging CRISPR gene editing could help grasp those rules.

Using two complementary approaches, the teams—one from the Lander lab, the other from that of Broad Core Institute Member and McGovern Institute for Brain Research investigator Feng Zhang—used CRISPR as a tool to systematically probe thousands of noncoding DNA sequences simultaneously (much as Broad groups did in the past with coding DNA). In the process, both identified several interesting genetic regulators, including ones millions of bases away from the genes they control.