Following 'regulations'

CRISPR study by Sanger Institute researchers and colleagues reveals new immune system regulators

Jeffrey Bouley
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HINXTON, U.K.—In some interesting CRISPR-related news, recent research (published Jan. 10 in the journal Cell) has led to a map of T cell regulation that could aid development of drugs that could activate the immune system. CRISPR is a gene-editing technology that enables researchers to cut DNA at any position in the genome, to create mutations and switch off specific genes, with CRISPR/Cas9 being the most commonly used technology right now.
Wellcome Sanger Institute scientists and their collaborators say they have created the first retroviral CRISPR/Cas9 gene-editing library to explore the regulation of mouse T cells, which are key cells in the immune system. The scientists have mapped what they say are the most important genes for controlling T helper cells and have identified several new potential regulatory genes, advancements that could help in the future development of new treatments to activate the immune system against infection or to attack tumor cells. Better understanding of what regulates T cell development could also help find new drugs against autoimmune diseases such as allergies or rheumatoid arthritis.
As Sanger’s Communications Department explains, the immune system protects the body against infection and tumors, and T helper type 2 cells (Th2) are a key component of this, releasing specific chemicals to tell the body to kill invaders. T helper cells are switched on when an invader is detected. They then need to develop down exactly the right pathway to best help remove that specific infection, a process known as differentiation. However, as the Sanger Institute points out, it is unclear exactly what signals activate these cells or tell them how to develop and which chemical signals to release.
To investigate this, the Wellcome Sanger Institute researchers and colleagues created a new genome-wide CRISPR library of 88,000 guides that enabled them to switch off each of the 20,000 genes from mouse Th2 cells. After mimicking an infection in cultured Th2 cells, they studied how switching off each single gene in the genome affected the activation or differentiation. They found many different genes involved in regulating Th2 development, and defined the gene regulatory network.
“This is the first ever unbiased genome-wide analysis of the activation and differentiation of T helper cells, helping us understand which signals are involved in immune system regulation. Our study shows that many different types of genes impact both activation and differentiation of these immune cells, indicating how closely linked those two processes are,” said Dr. Johan Henriksson, joint first author from the Wellcome Sanger Institute and the Karolinska Institutet in Sweden 
Tight control of the Th2 cells’ activation and differentiation is a critical concern because if the cells are not active enough, they won’t fight the illness; conversely, if they are too active, the body can attack itself in autoimmunity. Fortunately for this effort, the study identified several new regulatory genes, with the researchers making the discovery that the transcription factor PPARG is particularly important for regulating Th2 cells.
“In the past, immunologists have been investigating Th2 mostly one gene at time. In this study, we developed a new retroviral CRISPR library, which has enabled us to efficiently knock-out each individual gene in mouse T helper cells for the first time,” explained Dr. Xi Chen, joint first author from the Wellcome Sanger Institute. “We combined the CRISPR screen with other genomic technologies to gain a systematic overview of these immune cells. This has not only allowed us to identify genes involved in the regulation of Th2 cells, but could also be used to study other mouse immune cells and their regulation.”
Concluded Dr. Sarah Teichmann, the senior author from the Wellcome Sanger Institute and University of Cambridge: “This study will help drive forward our understanding of the immune system. We have created an atlas of the most important genes involved in the regulation of T helper cell immune response, and highlighted particular genes for further study. This openly available resource will be extremely useful for scientists studying the immune system, and could lead to finding new immune-activating therapeutics against tumors and infections, or for damping down the immune response to relieve allergies in the future.”
In other recent CRISPR news from the Wellcome Sanger team, November of last year saw them report on what they say is the largest study of CRISPR action to date, resulting in a method to predict the exact mutations CRISPR/Cas9 gene editing can introduce to a cell. Researchers at the Wellcome Sanger Institute edited 40,000 different pieces of DNA and analyzed millions upon millions of resulting DNA sequences to reveal the effects of the gene editing and develop a machine learning predictive tool of the outcomes. This is expected to assist researchers who are using CRISPR/Cas9 to research disease mechanisms and drug targets, enabling scientists to predict the best sequences to target to make CRISPR/Cas9 gene editing more reliable—and therefore cheaper and more efficient. The results of the study appeared in the journal Nature Biotechnology on Nov. 27.

Jeffrey Bouley

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