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CRISPR used to investigate non-coding regions of the genome

3 October 2016
Appeared in BioNews 871

Two teams of researchers have used CRISPR genome editing technology to identify 'non-coding' regions of the genome for the first time.

Non-coding DNA does not code for any known genes, but instead regulates the switching on and off of genes and is thought to play a major role in disease as well as responses to drug treatment.

'Ninety percent of the genetic variations that affect human disease are in the non-coding regions,' said Professor Eric Lander, founding director of the Broad Institute of MIT and Harvard and lead author of one of the two papers, both published in Science. 'But we haven't had any way to tell, in a systematic way, which regulators affect which genes.'

Both research groups used complementary CRISPR approaches to scan large regions of non-coding DNA sequences at once.

In the first study, carried out by the Zhang lab at the Broad, researchers used a CRISPR/Cas9 screen to create precise mutations in non-coding regions around three genes that are associated with resistance to chemotherapy.

The team identified hundreds of non-coding sites which, when mutated, caused reduced expression of the target genes NF1, NF2, and CUL3. In particular, they found that mutations to 24 non-coding regions around the CUL3 gene not only reduced gene expression, but also conferred resistance to vemurafenib, a cancer drug used in the treatment of melanoma.

The other study, led by Professor Lander, used a broader 'CRISPR interference' (CRISPRi) approach. The researchers used a 'dead' form of the Cas9 enzyme to silence non-coding sequences around two disease-related genes, GATA1 and MYC. Out of hundreds of possible regulatory regions, they found that only two were involved in GATA1 regulation, and only seven in MYC expression.

Both teams are optimistic about the potential of their findings to shed light on the importance of non-coding DNA in gene regulation.

'Compared to the sequences of protein-coding genes, we don't know much about non-coding regulatory elements,' said Dr Neville Sanjana, who worked in the Zhang lab. 'Our study and other gene-editing screens will enable us to discover the rules that govern these important parts of the genome.'

But first they need to scale up CRISPR technologies to scan larger regions of non-coding sequences. 'One of the huge challenges ahead is to extend this from one million to the full 3.2 billion bases in the human genome,' George Church, professor of genetics at Harvard Medical School, who was not involved in the study, told The Scientist.

CRISPR Screening Helps Parse Noncoding Genomic Regions
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High-resolution interrogation of functional elements in the noncoding genome
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Systematic mapping of functional enhancer-promoter connections with CRISPR interference
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Targeting the Noncoding Genome with CRISPR
The Scientist |  29 September 2016
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