Yang Shi received his PhD from New York University where he studied regulation of a multi-gene family in mice. He carried out postdoctoral research in the lab of Dr. Thomas Shenk at Princeton University where he discovered the transcription factor YY1 (Yin Yang 1 for its ability to both activate and repress transcription), which plays a critical role in many important biological processes. He began his independent research career at Harvard Medical School as an assistant professor and received tenure and full professorship in the Department of Pathology at Harvard Medical School in 2004. In 2009 he joined the Newborn Medicine Division of Boston Children’s Hospital. He is currently C. H. Waddington Professor of Pediatrics and Professor of Cell Biology at Harvard Medical School. His honors include Ray Wu Award (2009), election to the American Association for the Advancement of Science (2011, AAAS Fellows), American Cancer Society Research Professor (2012) and election to the American Academy of Arts and Sciences (2016).
His most significant and widely known scientific contribution is the discovery of the first histone demethylase LSD1, which overturned the 40-year-old dogma that histone methylation is irreversible. This groundbreaking discovery was published in Cell in 2004, and was selected by Cell as one of the 25 landmark publications over forty-year history of Cell. He also identified many additional histone demethylases, which belong to the JmjC domain-containing, dioxygenase family of enzymes. These discoveries not only provided critical novel insights into epigenetic regulation but also revealed new drug targets for cancer therapy. For instance, small molecules targeting LSD1 are now in clinical trials for AML. Excitingly, Yang’s most recent work also uncovered a role for LSD1 in immune checkpoint blockage, i.e., inhibition of LSD1 can turn “cold” tumor “hot”, thus enabling immune checkpoint blockage for cancers that otherwise are not responsive to immune therapy. This work laid the foundation for future combination therapies involving the use of inhibitors of epigenetic regulators such as LSD1 and checkpoint inhibitors for immune-resistant cancers.
Yang was also one of the first to describe the DNA vector-based RNAi technology, which is widely used as a means to study eukaryotic gene function. The LSD1 and the vector-based RNAi papers alone have garnered over 5,500 citations according to Google Scholar. He is also responsible for the discovery of the first reader modality that recognizes the methyl zero state on histone tails as well as a novel reader selective for a variant histone H3, which are key components in the chromatin network.