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Researchers Find the Unexpected from Their Map of the Mouse Functional Genome

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Only a small percentage of the mouse genome codes for proteins, and researchers don't have a thorough understanding of the function of much of the rest of it. To elucidate that portion, researchers at the Ludwig Institute for Cancer Research at the University of California, San Diego, published a study in Nature in July, in which they mapped 11 percent of the mouse functional genome, identifying more than 70 percent of conserved non-coding sequences as well as nearly 300,000 cis-regulatory elements in 19 different tissue and cell types. Using ChIP-seq, the researchers identified enhancers and promoters based on their chromatin modification patterns and then used different computational tools to identify co-regulated promoters and enhancers.

"Most of the newly identified regulatory elements are located far from the protein-coding genes, but they still control the tissue-specific and stage-specific gene expression," says Feng Yue, lead bioinformatician on the project. "So this study is going to greatly improve the annotation of the mammalian genome, and it has great resource value for understanding gene regulatory mechanisms."

The researchers were surprised to find that the majority of the conserved non-coding sequences they identified are located within cis-regulatory elements and that they have the potential to control gene expression, Yue adds. They also discovered that the majority of the cis-regulatory elements form large blocks of co-regulated elements that cover more than 40 percent of the mouse genome.

"We found that the median enhancer-to-promoter ratio in each block is almost six-to-one, suggesting a gene might be regulated by multiple enhancers," Yue says. "In addition, we found that these functional domains match well with the topological domains we defined recently in other work from our lab, suggesting that at least one function of the physical partition of the genome is to facilitate co-ordinated regulation of genes within the same genomic domains." The team identified large, megabase-sized local chromatin interaction domains in a previous Nature study that appeared in May.

Co-first author Yin Shen says there is potential for learning how to "fine-tune" gene expression. "It would be interesting in the future if we are able to manipulate gene expression by either deletion or addition of these sequences in the mouse genome instead of directly targeting that gene," she says.

The team plans to continue with the mapping effort, aiming to identify cis-regulatory elements in additional mouse developmental stages and tissues. "Many of these elements are tissue- and developmental stage-specific, especially those involved in regulating early embryonic development and body plan, and remain to be identified," Shen says.

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