We are interested in understanding how epigenetic chromatin domains are assembled and stably propagated.

Research in the Moazed lab is focused on the remarkable ability of heterochromatic domains of DNA to heritably silence genes and transposons. These functions of heterochromatin are indispensable for maintenance of cell identity and genome stability, and their loss is prominently associated with developmental abnormalities, cancer, and age-associated neurodegenerative diseases. Our lab has demonstrated that nuclear RNAi and other RNA decay pathways play critical roles in heterochromatin assembly and elucidated how the RNAi machinery localizes to specific chromosome regions to establish heterochromatin. We have further demonstrated that although heterochromatin can mediate its own epigenetic propagation independently of DNA sequence, RNAi and specific DNA sequences are also crucial for heterochromatin maintenance. By deciphering the underlying mechanisms that assemble and epigenetically maintain heterochromatin, our studies provide a foundation for understanding how heterochromatin contributes to epigenetic maintenance of cell identity and how it decays during aging and in diseases such as cancer and neurodegeneration.

Selected References:

Holoch D, Moazed D (2015). RNA-mediated epigenetic regulation of gene expression. Nature Reviews Genetics 16, 71-84.

Ragunathan K, Jih G, Moazed D (2015). Epigenetic inheritance uncoupled from sequence-specific recruitment. Science 348 (6230):1258699.

Wang X, Moazed D (2017). DNA sequence-dependent mechanism for epigenetic inheritance of H3K9 methylation. Science 356, 88-91.

Jih G, Iglesias N, Currie MA, Bhanu NV, Paulo JA, Gygi SP, Garcia B, Moazed D (2017). Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription. Nature 547, 463-467.

Yu R, Wang X, Moazed D (2018).  Epigenetic inheritance mediated by coupling of RNAi and histone H3K9 methylation. Nature 558, 615-619.

Iglesias N*, Currie M*, Jih G, Paolo JA, Suiti N, Kalocsay M, Gygi SP, Moazed D (2018).  Automethylation-induced conformational switch in Clr4/SUV39H maintains epigenetic stability. Nature 560, 504-508.