In a recent series of online workshops organized by Tsinghua University and Science/
AAAS, scientists explored alterations in gene activity caused by mechanisms beyond
changes to the genetic sequence.Modifying DNA with organic additions, such as a methyl group, can change
the function of the molecule. Such epigenetic changes impact a wider range of
biological processes, from DNA maintenance and immune-cell memory to gene
regulation and disease. Scientists use a variety of methodsóincluding structural
biology, gene knockouts, and moreóto explore the impact of epigenetic processes.
On September 23, 2021, Haitao Lióassociate director of the Beijing Advanced
Innovation Center for Structural Biology and associate dean of the School of
Medicine, Tsinghua Universityóopened the session on structural and functional
work on DNA methylation and its regulation.
The first speaker, Dinshaw Patel, a structural biologist at Memorial Sloan
Kettering Cancer Center in New York, described the work of various investigators
on DNA methyltransferases. As he explained, conformational changes to these
molecules modulate their performance of various functions, such as DNA
maintenance, which can impact human disease.
The next speaker, Bing Zhu, investigator and deputy director of the Institute of
Biophysics at the Chinese Academy of Sciences, discussed his laboratoryís work
on DNA methylation. For example, he explained how changes in DNA methylation
patterns arise in aging and tumorigenesis. He also described the role of
methylation in creating memory B cells in the immune system, observing, ìWe have
profound transcriptional memory in memory B cell activation.î
On October 21, 2021, Yang Shiówho discovered the first histone demethylase,
LSD1 (lysine-specific demethylase 1)óexplained how this work precipitated
potential cancer treatments. Now a principal investigator at the Ludwig Institute for
Cancer Research at the University of Oxford, United Kingdom, he studies the roles
of chromatin and RNA modifications in cancer. He remarked, ìWeíre very interested
in understanding immune checkpoint blockage through manipulating chromatin
regulators.î For example, he showed that LSD1 can make a tumor more responsive
to immune therapy. In addition, he has used RNA interference to study the function
of genes in eukaryotes.Continuing the discussion about chromatin, Karolin Lugeróthe Jennie Smoly
Caruthers Endowed Chair of Biochemistry at the University of Colorado Boulderó
talked about the evolution of nucleosomes, which ìare targets of epigenetic
control,î she said. Finding histone-like proteins in the single-celled archaea allowed
her team to compare eukaryotic and noneukaryotic chromatin. Using gene knockout
studies, her lab showed that these histone-like proteins are crucial for infectivity by
a virus.
In the last session, held on December 2, 2021, Cynthia Wolbergeróprofessor
and director of the Department of Biophysics and Biophysical Chemistry at the
Johns Hopkins University School of Medicineódescribed the role of reversible
posttranslational modifications of histone residues in gene regulation. For example,
she showed how large modifications, such as adding a ubiquitin molecule to a
histone, impact transcription regulation. She delved deeper into the structural and
biochemical evidence for how ubiquitination of histone H2B stimulates specific
methyltransferases, and concluded with a discussion of the role of impaired
regulation of H2B-specific deubiquitinating enzyme inhibitors in cancer.
To close this lecture series, cancer researcher Peter Jones, chief scientific officer
at the Van Andel Institute in Grand Rapids, Michigan, updated participants on
the methylation of DNA in nucleosomes. These processes depend on a specific
combination of methyltransferases and accessory proteins. Employing cryogenic
electron microscopy and gene knockouts, Jones has depicted the structure and
function of such complexes. He concluded, ìItís been a very interesting project in
which we relate human disease to biological processes to chromatin studies and
nucleosome function.î
As these lectures demonstrate, epigenetics can be harnessed to study the basic
mechanisms of biology as well as elucidate disease processes. Such studies could
even be used to develop treatments for various diseases, including cancers.Advertorial
Tsinghua-Science Workshops: Epigenetics Structure and Function
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IMAGES PROVIDED BY TSINGHUA UNIVERSIT YWorkshop speakers. Top row (L to R): Dinshaw Patel, Bing Zhu ,Yang Shi. Bottom row (L to R): Karolin Luger, Cynthia Wolberger, Peter Jones.Sponsored by1224Product.indd 1531 12/15/21 7:48 AM