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Genetics: ENCODE expands the encyclopaedia of regulatory elements

Nature

July 30, 2020

An online registry of over 1,200,000 human and mouse candidate functional elements that regulate genes is presented as part of the third phase of the ENCyclopedia of DNA Elements (ENCODE) project. The findings, included in a collection of 14 papers in Nature, Nature Methods and Nature Communications, provide new insights into genome organization and function.

Established in 2003, the ENCODE project aims to develop a comprehensive map of the functional elements — regions of DNA that code for molecular products or biochemical activities with roles in gene regulation — of the human and mouse genomes.

In an overview paper in Nature, Zhiping Weng and colleagues describe the generation of nearly 6,000 new experiments (4,834 involving human samples and 1,158 with mouse samples) that extend the earlier phases of ENCODE. Whereas much of the research during the previous phases was conducted using model cell lines, phase III includes 503 cell or tissue types from more than 1,369 biological sample sources. An online registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements (regions of non-coding DNA that regulate the transcription of genes), covering 7.9% and 3.4% of their respective genomes, has also been curated from the millions of elements mapped by ENCODE. Other papers in the collection use the ENCODE datasets to reveal the principles that govern how some of these functional elements work. For example, Michael Snyder and colleagues mapped the interactions of chromatin (a complex of DNA and proteins) in 24 human cell types and found that differences in chromatin looping between cell types can affect gene expression.

As part of the package, the regulatory role of cis-regulatory elements during prenatal mammalian development is explored in mice. Three papers published in Nature present information on fetal mice during eight developmental stages. In two of these papers, Bing Ren and colleagues and Joseph Ecker and colleagues demonstrate that the human equivalents of some enhancer elements (regulatory DNA sequences that can enhance the transcription of a gene) that are active in specific tissues in mice during development are enriched for disease-associated genetic variants. The findings may provide a starting point for the investigation of regulatory elements involved in human developmental disorders.

In an accompanying Perspective, also published in Nature, Michael Snyder and colleagues note that elements that govern genome control and function are densely encoded in the human genome. However, despite the discovery of a large number of these elements, many elements that affect particular cell types or states remain to be identified. As part of ENCODE phase IV, considerable effort is therefore being devoted to expanding the cell types and tissues analysed.

doi: 10.1038/s41586-020-2493-4

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