The organization and packaging of the genome within the nucleus is crucial for its function. An important and universal division is the separation of active and inactive chromatin. Constitutive heterochromatin is a poorly understood component of inactive chromatin that covers 20-50% of animal genomes. It is characterized by H3K9 methylation, binding of heterochromatin protein HP1, high compaction, enrichment for repetitive elements, and low transcriptional activity. Constitutive heterochromatin has both regulatory and structural roles and its loss disrupts chromosome organization, activates repetitive elements, alters gene expression, and causes genome instability. Not surprisingly, heterochromatin dysfunction is associated with human disease, including cancer. Despite its importance, our understanding of how constitutive heterochromatin forms and functions is extremely limited. To address this, we study how a network of heterochromatin proteins including HP1, together with small RNA pathways, collaborates in heterochromatin formation and function. This work uses a range of approaches including super-resolution microscopy, high-throughput assays of chromatin composition and architecture, and RNAi genetic interaction screening to identify novel heterochromatin components.
