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Computational Method Identifies Chromatin Loops at Single-Cell Resolution

Dr. Hu and collaborators developed a new method, SnapHiC, to study chromatin spatial organization in single cells to help reveal mechanisms governing gene regulation and disease etiology.

08/26/2021




According to new findings published in Nature Methods, a team of researchers co-led by Ming Hu, PhD, Department of Quantitative Health Sciences, and Bing Ren, PhD, University of California, San Diego, have developed a novel computational method, called SnapHiC, to study chromatin spatial organization in single cells of complex human tissues.

Chromatin is the material within chromosomes that contain DNA and proteins. The 23 pairs of human chromosomes, which measure six-feet long in total length, are packed into an extremely small cellular compartment called the nucleus. In order to fit within this tiny space, the chromatin fibers have to be folded very carefully in a way that does not impede critical cellular processes, such as gene expression and DNA replication. Dysregulation of chromatin folding has been implicated in various diseases.

“While single cell genomics technologies exist to map chromatin architecture in individual cells of complex tissues, it is still challenging to map chromatin loops at high resolution,” said Dr. Hu. “We developed a computational method named SnapHiC that harnesses data generated from existing technologies to more accurately identify chromatin loops at high resolution in single cells.”

SnapHiC demonstrates high sensitivity and utility for complex tissues

The researchers benchmarked the performance of SnapHiC against existing methods using sample sizes ranging from tens to several hundred cells. They found that SnapHiC could identify more chromatin loops for all sample sizes than conventional approaches developed for bulk samples. In addition, SnapHiC detected previously identified loops from bulk cell data with as few as 75 or 100 cells, while the other methods required at least four times more cells to find the same loops. 

“Our data demonstrate SnapHiC’s high sensitivity, which is particularly useful since collecting a large number of cells can be cost prohibitive as well as impractical for rare cell types found in complex tissues,” noted Dr. Hu.

To further explore SnapHiC’s utility for complex tissues, they applied SnapHiC to cells from the prefrontal cortex of the human brain. The researchers found chromatin loops specific to individual brain cell types that correlated with gene expression and epigenetic markers (external modifications to DNA that tell genes to switch on or off).

“Chromatin loops enable regulatory DNA sequences to contact genes and influence their expression, so being able to identify and study these loops can provide insights into the genes involved in various diseases and conditions,” said Dr. Ren, a co-principal investigator of the five-year, $6.5 million grant from the National Institutes of Health that funded this research. Dr. Hu is a co-investigator on the grant, which is part of the 4D Nucleome program.

Dr. Ren continued, “Altogether, our study demonstrates that SnapHiC has the potential to facilitate the study of gene regulation mechanisms and causes of disease in a cell type-specific manner.”

Miao Yu, PhD, a former postdoctoral fellow in Dr. Ren’s lab and currently an assistant professor at Fudan University in China, and Armen Abnousi, PhD, a former postdoctoral fellow in Dr. Hu’s lab, are co-first authors on the study.




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