Illuminating dark matter in human DNA

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University of California San Diego researchers have created a single-cell chromatin Atlas for the human genome. Chromatin, a complex of DNA/protein found in eukaryotic cell cells, is open to certain configurations within the cell nuclei. These regions are key genes regulatory elements. It would be a significant step towards understanding the role of non-coding DNA (gene regulatory elements) in human health and disease.

These findings were published online in Cell's November 12, 2021 issue.

Scientists consider the human genome to be the "book of living." Or at the very least, unread. Science has famously estimated that there are approximately 20,000+ protein-coding genes needed to make a human being. However, this estimate doesn't really explain how the process works.

"The human genome was sequenced twenty years ago. However, interpreting the meaning of that book of life is still difficult," stated Bing Ren, Ph.D. director of the Center for Epigenomics and professor of cellular medicine at UC San Diego School of Medicine. He is also a member of UC San Diego's Ludwig Institute for Cancer Research.

"The main reason is that more than 98 per cent of human DNA sequences are non-protein-coding and we don't yet have a genetic book to unlock the information contained in these sequences."

It's similar to knowing the chapter titles, but the rest of the pages are still blank.

Ren and his colleagues have been capturing the efforts to fill in the gaps in an international effort called Encyclopedia of DNA Elements (ENCODE). They have focused on the role and functionality of chromatin, which is a complex of DNA, proteins and other substances that forms chromosomes in the nuclei of eukaryotic cell nuclei.

The DNA encodes the cells' genetic instructions. Histones, the major proteins found in chromatin, are responsible for tightly packaging the DNA into a compact format that fits inside the cell nucleus. There are approximately six feet of DNA in each cell nucleus, and about 10 billion miles within each human body. Modifications in the way chromatin bundles DNA DNA are linked to DNA replication and gene expression.

Ren and his collaborators began their work with mice. They then turned their attention towards a single-cell Atlas of Chromin in the Human Genome.

The researchers applied assays on more than 600,000.000 cells taken from 30 types of adult human tissues from multiple donors. They then combined that data with similar data from 15 types of fetal tissue to determine the status chromatin in approximately 1.2 million candidate regulatory elements in 222 cell types.

Sebastian Preissl, co-author of the study, is associate director for Single Cell Genomics at UC San Diego Center for Epigenomics. This collaborative research center performed the assays.

Non-coding regions of non-coding genetic DNA regulate transcription. This is the process of converting a portion of DNA into RNA. Transcription is an essential step in the transformation of genetic information into action.

"Studies over the past decade have shown that sequence variations in noncoding DNA are a major driver of multi-genic traits in humans, such as diabetes, Alzheimer’s disease, and autoimmune disorders," stated Kyle J. Gaulton (Assistant Professor in the Department of Pediatrics at UC San Diego School of Medicine).

Kai Zhang, Ph.D. is a co-first author and a postdoctoral fellow at the Department of Cellular and Molecular Medicine. "A new paradigm helps explain how noncoding variants contributes to diseases." Kai Zhang said. The lack of cell-type-specific maps for transcriptional regulatory elements within the human genome is a major obstacle to unlocking the functions of noncoding risk variants.

Ren said the new findings identify disease-trait-relevant cell types for 240 multi-genic traits and diseases, and annotate the risk of noncoding variants.

"We believe this resource will greatly assist the study of mechanism across many human diseases over many years."

Preissl stated that the chromatin Atlas will allow scientists to identify tissue-specific differences between cell types found in different tissues. This includes fibroblasts and immune cells, as well as endothelial cells.

Further Cell-type-specific insights into the role of risk factors in coronary heart disease are available

Kai Zhang et. al., A single-cell Atlas of Chromatin Accessibility in the Human Genome, Cell (2021). Information from Cell Kai Zhang et. al., A single-cell Atlas of Chrin Accessibility in the Human Genome, (2021). DOI: 10.1016/j.cell.2021.10.024