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USC Researchers Discover Epigenetic Control of Infection-Fighting Blood-Cell Production

 Si-Yi Chen, M.D., Ph.D.

Researchers at the Keck School of Medicine have discovered how a particular enzyme results in modifications to DNA proteins, playing an important role in the development of B cells, the white blood cells that produce antibodies to fight infectious diseases, and in the regulation of gene transcription, or copying.  This epigenetic research marks a major advance in understanding blood-cell production, and may hold promise for the development of treatments for blood-borne malignancies.

Epigenetics, an increasing focus of scientific research, is the study of gene expression by modifications to the DNA molecule and its associated histones, the proteins contained in the nucleus of cells that are responsible for packaging and ordering the DNA. Histones affect the way the genomic code is translated into proteins, determining cell development, identity, and function. 

Si-Yi Chen, M.D., Ph.D., and professor of Immunology and Molecular Microbiology at the Keck School and the USC Norris Comprehensive Cancer Center, served as the principal investigator of the study, “Control of B Cell Development by the Histone H2A Deubiquitinase MYSM1.”  This important discovery was published in the Dec. 8 online issue of Immunity. Two researchers in Chen’s lab also contributed significantly to the findings: First author Xiao-Xia Jiang, a postdoctoral student, and second author Quan Nguyen, a graduate student.

Researchers long have known that histones play a role in gene regulation. They also have known that histones are subject to modifications, which affect the copying and translation of genes, blood-cell generation, and tumor generation. But until now, they have lacked an understanding of how these processes occur.

One common histone modification is ubiquitination, in which the protein ubiquitin attaches to histones, regulating gene transcription. Using mouse models, Chen’s lab discovered that the histone ubiquitin-specific enzyme MYSM1, which removes ubiquitin from modified histones, is necessary for B-cell development and gene transcription.

“For the first time we found that MYSM1 is essential for the physiological development of B cells by turning on key target genes,” said Chen. “And, this enzyme is one of a new class of histone deubiquitinases that remove ubiquitin from histones. Understanding the role of this molecule opens a door to understanding the mystery of blood-cell formation controlled by other epigenetic modifiers in this class.”

The research results also are expected to lead to information about the process by which normal blood cells are converted into malignant cells such as lymphoma and leukemia, and enable researchers to develop potential treatments for such malignancies.

These findings follow research about the removal of ubiquitin from protein, which Chen has been conducting for many years. Most significant of his past work is that such deubiquitination plays a major role in protein function related to inflammatory signaling and immune response. He also is engaged in creating technologies and approaches to developing immunotherapies against cancer.

Building on the most recent work, Chen’s next study examines how MYSM1 could regulate the proliferation and survival of normal and malignant human B-cells.

“This is part of understanding the fundamental mechanisms of epigenetic regulation, of how genes are targeted and turned on or off with significant biological function and consequences,” he said.

The research was supported by grants from the National Institutes of Health and Leukemia & Lymphoma Society
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