Epigenetic changes determine the fate of a B cell

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BOSTON – B cells are the immune cells responsible for making antibodies, and most B cells, called B2 cells, produce antibodies in response to a pathogen or vaccine, providing defense and immunity against them. infections. But a small subset of long-lived B cells, called B1 cells, are quite different from their short-lived cousins, B2 cells. Instead of producing antibodies in response to invaders, they spontaneously make antibodies that perform vital housekeeping functions, such as removing wastes like oxidized LDL cholesterol from the blood.

Like all cells in the body, cells B1 and B2 have the same DNA, and therefore the same set of starting instructions. It is through epigenetic modifications, which open and close different areas of the genome to the machinery that reads genetic instructions, that the same genome can be used to create unique instructions for each type of cell. Understanding how different epigenetic landscapes – changes in instructions – enable these differences in such similar cells is both an important fundamental question in immunology and can help scientists better understand diseases related to B cell dysregulation.

Shiv Pillai, MD, PhD, senior fellow of the Ragon Institute of MGH, MIT and Harvard, studied the DNA changes present in both types of cells during different stages of development to identify an epigenetic signature that can determine whether a cell becomes a B1 or a B2 cell. This work was recently published in the journal Nature Communication.

“Through our analysis, we discovered that the fate of a B cell is determined by epigenetic changes induced by a protein called DNMT3A”, explains Vinay Mahajan, MD, PhD, pathology instructor at the Ragon Institute and first author of the article. “Genetic studies in humans link genomic regions with these markers to a variety of immune-mediated disorders.”

The team studied CpG methylation, a type of epigenetic modification that opens up specific areas of DNA and marks regulatory elements that can turn genes on or off. They discovered a set of regulatory elements with unique characteristics in these B1 and B2 cells. In most cases, methylation of CpGs is permanent and, once added, is even passed on as the cell replicates. But in B cells, the DNMT3A protein had to continually work to maintain these epigenetic changes. If DNMT3A were removed from B1 cells, epigenetic changes would be lost and chronic lymphocytic leukemia (CLL), a cancer caused by the uncontrolled replication of B1 cells, would appear.

“These unique B1 cells are vitally important to our ability to stay healthy,” says Pillai. “The antibodies they create help prevent blood clots and heart attacks. At the same time, understanding what genetic factors regulate them can help us better understand what happens when their regulation goes out of order and leads to CLL and d ‘other diseases. ”

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The co-authors are Hamid Mattoo, PhD, Na Sun, Vinayak Viswanadham, Grace J. Yuen, PhD, Hugues Allard-Chamard, MD, PhD, Maimuna Ahmad, Samuel JH Murphy, Annaiah Cariappa, MD, and Yesim Tuncay.

This work was supported by the National Institutes of Health and the Ragon Institute Strategic Funding.

About the Ragon Institute of MGH, MIT and Harvard

The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a donation from the Phillip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission between these institutions to harness the immune system to fight and cure human disease . With a focus on HIV and infectious diseases, the Ragon Institute attracts scientists, clinicians and engineers from a variety of backgrounds and fields of expertise to study and understand the immune system for the benefit of patients. patients. For more information visit http://www.ragoninstitute.org

About Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is Harvard Medical School’s first and largest teaching hospital. The Mass General Research Institute leads the nation’s largest hospital-based research program, with annual research operations of over $ 1 billion, and includes more than 9,500 researchers working in more than 30 institutes, centers and departments. In August 2020, Mass General was named # 6 in the US News & World Report list of “America’s Best Hospitals”.


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