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
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
“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