Eukaryotic genomes contain numerous repetitive DNA sequences that are assembled into heterochromatin, which plays a critical role in preventing recombination between repeats and silencing repeat expression to maintain genome integrity. Heterochromatin also regulates gene expression programs to determine cell identity, which can be stably inherited by subsequent generations. Consequently, misregulation of heterochromatin has been associated with many human diseases. Conversely, modulating heterochromatin enhances cancer immunotherapy because repeat expression makes tumor cells more vulnerable to recognition and elimination by the immune system. Our lab's long-term goal is to understand the mechanisms that regulate heterochromatin formation and epigenetic inheritance, leading to the development of new therapeutic strategies for treating human diseases.
Mechanism of heterochromatin assembly
Our primary goal is to investigate how histone-modifying activities coordinate during heterochromatin formation in the fission yeast Schizosaccharomyces pombe. To identify new pathways that regulate heterochromatin formation, we have developed a high-throughput screening system using the fission yeast deletion library. Additionally, we employ biochemical and genomic approaches to uncover the underlying molecular mechanisms.
Mechanism of histone-based epigenetic inheritance
During DNA replication, parental histones, which contain the original histone modifications, are deposited back into their original locations and equally segregated onto both daughter strands to direct the formation of nucleosomes. The existing modifications on parental histones then serve as templates to restore the original histone modification profiles on both replicated chromatids. We use fission yeast heterochromatin as a model to study how this chromatin state is inherited during DNA replication.
Oncogenic histone mutations
Recent high-throughput sequencing analyses have revealed high incidences of somatic histone lysine-to-methionine (K-to-M) mutations in multiple cancers. We have established fission yeast models in which the introduction of H3K9M or H3K36M transgenes abolishes the methylation of corresponding lysines on wild-type histones, thereby recapitulating the effects of these mutations in cancer cells. We are examining how these mutations regulate cellular functions and identifying pathways that can be targeted to selectively kill cells containing these oncogenic histone mutations.
Regulation of endogenous retroviruses for cancer immunotherapy
Endogenous retroviruses (ERVs) are mobile genetic elements that have colonized organismal genomes throughout evolution. Host cells have evolved highly conserved defense mechanisms to silence ERV expression and mobilization due to their threat to genome integrity. However, ERV activation can also make tumor cells prone to recognition and elimination by the immune system. We study the basic mechanisms that regulate ERV silencing and activation, which are critical for designing new therapeutic approaches for cancer immunotherapy.