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Science Papers Explore Nanopore Approach to Read Proteins, Role of Noncoding DNA in Forming 3D Structure

A nanopore-based system for reading individual proteins at single-amino acid resolution is described in this week's Science. The approach, developed by a team led by Delft University of Technology scientists in the Netherlands, involves pulling a DNA-peptide conjugate through a biological nanopore by a helicase walking on the DNA section. Reading the ion current signal through the nanopore, the researchers write, enables discrimination of single-amino acid substitutions in single reads. Notably, the peptide reads can be rewound, allowing for numerous independent reads of the same molecule. "Although it is not presently capable of de novo protein sequencing, this nanopore peptide reader provides site-specific information about the peptide's primary sequence that may find applications in single-molecule protein fingerprinting and variant identification," they write.

Noncoding sequences of the human genome are known to be critical to many biological processes, yet most of genome remains unannotated. Given the role of the genome's 3D organization in the regulation of transcription and other cellular functions, a group led by scientists from the University of California, San Diego, aimed to investigate the importance of noncoding sequences in forming and maintaining proper 3D chromatin structure, particularly ones not marked by any epigenetic signal or annotated with any functional unit. As the researchers report in this week's Science Advances, they began by identifying noncoding regions involved in many chromatin contacts — termed hubs — then performed CRISPR library screening to identify dozens of these hubs that are essential for cell growth and survival. Hi-C and single-cell transcriptomic analyses also showed that the deletion of these hubs could significantly alter chromatin organization and affect the distal genes expression. "This study revealed the 3D structural importance of noncoding loci that are not associated with any functional element, providing a new mechanistic understanding of disease-associated genetic variations," the study's authors write. "Furthermore, our analyses also suggest a possible approach to develop therapeutics targeting disease-specific noncoding regions that are critical for disease cell survival."