Cells must continuously balance epigenetic stability with the capacity to adapt to environmental stress. This balance becomes especially critical during long-term environmental challenges, when the chromatin landscape must re-organize to permit adaptation to stress without compromising long-term fidelity.

In my talk, I will focus on the Suv39 family of histone methyltransferases which are classically known for their role in establishing heterochromatin in eukaryotes by histone H3 lysine 9 tri-methylation (H3K9me). Using the fission yeast as a mechanistic foundation, we recently showed that long noncoding RNAs (lncRNAs), together with RNA quality control complexes, nucleate the Suv39 homolog, Clr4, at heterochromatic regions. Iterative cycle of H3K9 deacetylation and methylation spreads the H3K9me domains and establishes heterochromatin at repetitive elements. Interestingly, in a previous study, we also discovered a new euchromatic function for Suv39/Clr4 in fission yeast cells exposed to persistent stress. We found that Clr4, in concert with RNA processing machinery, are co-opted and deployed to euchromatic parts of the genome to creating a window of epigenetic pliability that enables adaptive transcriptional responses. Considering the conservation of these proteins from yeast to human cells, we hypothesized that Suv39 proteins also may play a similar role in human cancers. I will present our unpublished work, where we tested the conservation of this Suv39 function in human cancer cells. Overall, these studies reveal a unified framework of stress-induced phenotypic plasticity in eukaryotes and illustrate how modeling stress in yeast cells can provide key insight into mechanisms that govern treatment resistance in human cancers.

Mo Motamedi is James & Patricia Poitras Endowed Chair in Cancer Research at Krantz Family Center for Cancer Research and Harvard Medical School. He is a molecular biologist whose work integrates RNAi, chromatin biology, cancer cell-state plasticity, genome evolution, and systems biology.

He grew up in Vancouver BC, where he completed his undergraduate degree from UBC. He then completed his PhD at the University of Alberta in Edmonton, focusing the mechanism of homologous recombination using E. coli as a model. His PhD work provided the first physical evidence for the occurrence of a replication-dependent double-strand break-repair (DSBR) mechanism in any organism. Initially postulated by Joshua Lederberg in 1955, direct physical evidence for the existence of a replication-dependent DSBR mechanism was missing. Using lambda as the DNA substrate for homologous recombination in E. coli and the classic density gradient experiments pioneered by Meselson and Stahl, his PhD proved that a replicative recombination system operates in wild-type E. coli in parallel to the classic break-join mechanism.

He then moved to Boston first as an NSERC and later as a CIHR postdoctoral fellow at Harvard Medical School in the laboratory of Danesh Moazed to work on RNAi and chromatin. His work established the fission yeast as a model organism in the Moazed Lab and led the effort in understanding how noncoding RNAs (ncRNAs) regulate the epigenetic inheritance of chromatin states using the fission yeast centromeres as a model. His postdoctoral work identified a complex network of physical interactions among small noncoding RNAs, nascent long ncRNAs (lncRNAs), RNAi and heterochromatin complexes, all of which are tethered to chromatin via tri-methylated lysine 9 of histone H3 (H3K9me). This research led to proposal of the Nascent Transcript Model according to which nascent lncRNAs tethered to chromatin provide a structural platform for the inheritance of epigenetically heritable chromatin domains. This model now serves as a general molecular blueprint for RNA-dependent chromatin modification pathways in eukaryotes.

His laboratory at the Krantz Family Center for Cancer Research at MGH and Harvard Medical School is chiefly focused on how epigenetic states are established, maintained and propagated through cell division. His lab uses the fission yeast as a model to uncover fundamental principles about these mechanisms and test the conservation of these findings in human cancer cells with hope of finding novel therapeutic strategies. Recently, his lab has also developed an interest in how genome evolution can shape gene regulatory networks and how disruption to these systems can lead to a disease state like cancer. He has received several awards and accolades including the James & Patricia Poitras Endowed Chair in Cancer Research from MGH, American Cancer Society Research Scholar, and the V Foundation Scholar Award. He is a member of the Ludwig Center at Harvard, American Cancer Society Cancer Stem Cell Consortium, Harvard Medical School Initiative for RNA Medicine, the Program for Genetics and Genomics at Harvard Medical School, and a member of the American Cancer Society’s RNA mechanisms in Cancer (RMC) grant review panel.