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DNA Barcoding at the Protein Level Identifies Key Cancer Immunity Genes



A novel technology for simultaneously analyzing the functions of hundreds of genes at single-cell resolution has been developed by scientists at Mount Sinai Hospital. The method relies on a barcoding approach using a novel protein.

Since the sequencing of the first human genome in the early 2000s yielded a lot more than 20,000 protein-coding genes, scientists were not yet able to characterize the many functions of individual genes. Without this information, our understanding of how the human genome works ̵

1; and how that knowledge can be used to predict, prevent, treat, and even cure disease – is limited.

In 2012 and 2013, scientists established a new approach to gene editing called CRISPR, which can be used to determine gene function. CRISPR has taken the scientific world by storm, but researchers were still challenged to use CRISPR to study the many thousands of genes and their many potential roles.

Pro-codes

The Technology of Medicine at Mount Sinai, developed by scientists at the Icahn School, helps solve the genomic challenge of analyzing the genome on an unprecedented scale. The research, led by postdocs Aleksandra Wroblewska, Ph.D. and Maxime Dhainaut, Ph.D., is a novel tool for cataloging and tracking various CRISPRs using synthetic proteins called epitopes.

The protein barcodes called Pro-Codes make it possible to use hundreds of CRISPRs together. Gene

While there are already technologies to pool CRISPRs, these approaches are heavily dependent on DNA as a barcode and only allow an insight into gene function. The Pro Code technique has allowed researchers at Mount Sinai to show researchers how to more fully characterize the biological effects of a gene.

Target for Cancer Immunotherapy

In the study, researchers used pro-code technology to search for genes that need to protect the immune system from cancer. They generated CRISPRs to target the deletion of putative immunoregulatory genes and paired them with the pro-codes.

Pro-code / CRISPR libraries were then introduced into breast cancer cells, and the tumors were challenged with killer T-cells designed to detect the cancerous cells. Most cancer cells were rapidly eliminated by the T cells, but there were some cells that resisted death.

The pro-code technology helped determine which genes in the resistant cells have been lost to the immune system. The studies also identified a negative regulator of the immune checkpoint PD-L1, an important clinical target of cancer immunotherapy.

"There is still much work to be done to fully understand the human genome, we still do not know what most genes do and how they are linked." "Pro-code technology could be one of the primary goals of Accelerating the Post-Genome Era: Annotating the Human Genome This discovery will be the key to discovering disease-causing genes that could lead to new drug targets, and it has already given us new insights into cancer immunology. "

Senior author said Brian Brown, Ph.D., Associate Professor of Genetics and Genomics and Associate Director of the Immunology Institute at the Icahn Institute.

Aleksandra Wroblewska, Maxime Dhainaut, Benjamin Ben-Zvi, Samuel A. Rose, Eun Sook Park, El Ad David Amir, Anela Bektesevic, Alessia Baccarini, Miriam Merad, Adeeb H. Rahman, Brian D. Brown
Protein Barcodes Enable High-Dimensional Single Cell CRISPR Screens
Cell (2018). DOI: 10.1016 / j.cell.2018.09.022


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