Yang Shi received his PhD from NYU Medical Center and postdoctoral training with Dr. Tom Shenk at Princeton University where he discovered the transcription factor YY1. He began his independent research career at Harvard Medical School as a tenure track assistant professor in 1991 and received tenure and full professorship in the Department of Pathology at Harvard Medical School in 2004. In 2009 he joined Boston Children’s Hospital where he held a Merton Bernfield Professorship in the Department of Medicine and was also professor of Cell Biology of Harvard Medical School, where he was honored with the inaugural C. H. Waddington Professorship of Pediatrics in 2018. He joined Oxford University in 2020 and is currently Professor of Epigenetics of Oxford University and member of the Ludwig Cancer Research. His honors include election to the American Association for the Advancement of Science (2011), The Ellison Medical Foundation Senior Scholar in Aging (2012), American Cancer Society Research Professor (2012), election to the American Academy of Arts and Sciences (2016), election to EMBO (2022), to AACR Academy (2022), the National Academy of Medicine (2022) and UK Academy of Medical Sciences (2023).
For the past three decades, Shi has been investigating fundamental mechanisms underlying transcription and chromatin regulation. He is responsible for the discovery of the first histone demethylase (LSD1) in 2024, elucidation of its mechanism of action and roles in heterochromatin and DNA damage regulation and is one of the main contributors to the subsequent discovery and characterization of many additional demethylases, thus changing the long-held paradigm that histone methylation is irreversible. Shi’s groundbreaking discovery re-ignited tremendous interest in the field to return to the question of whether DNA methylation, one of the most stable epigenetic modifications, was likewise reversible. Many labs were involved in the search for DNA demethylases, and these efforts culminated in the 2009 discovery of the TET enzyme by Anjana Rao and colleagues, which mediates the first step of a multi-step process that leads to effective DNA demethylation. These discoveries have revealed the dynamic nature of epigenetic regulation and have important biological implications. Histone and DNA methylation are recognized by proteins termed “readers”, which are effectors that implement the downstream functions of various epigenetic modification events. Shi has also made important contributions to the discovery of novel readers that recognize various methylation states of canonical and variant histones, including the founding member of a family of proteins that specifically recognize lysine methyl zero state of histone, providing additional insights into histone methylation recognition mechanisms. Importantly, many demethylases and readers are linked to human diseases including neurological dysfunction and Shi lab provided the first link between histone demethylation defects and X-linked intellectual disability and explored the underlying mechanism by generating and analyzing corresponding mouse models. Shi’s work also links dynamic histone methylation regulation to cancer. His more recent work demonstrating that targeting epigenetic regulators such as LSD1 enables immune checkpoint blockade may benefit patients who are otherwise resistant to this novel immune therapy. This discovery, together with his finding that combinatorial use of LSD1 and HDAC inhibitors induces therapeutic differentiation of DIPG, a deadly pediatric glioma, have important clinical implications for cancer treatment. Indeed, Shi’s discoveries are being explored for translational and drug discovery efforts both by academic institutions and pharmaceutical/biotech companies, with small molecules targeting LSD1 for neurological disorders and blood cancer now in phase II/III clinical trials. Additionally, combination therapies using LSD1 inhibitors together with anti-PD1 to treat refractory lung cancers have also entered phase II clinical trials. In sum, Shi’s discoveries not only have revealed fundamental principles of epigenetic regulation but have also enabled new therapeutic efforts, which ultimately will benefit patients worldwide. Shi has co-authored 221 original research publications and reviews.
