HP1-mediated Genome Stability in Normal Brain Development, Structure & Function

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While epigenetic modifications are typically initiated through recognition by a transcription factor to its cognate recognition sequence, it is the propagation of structural changes in chromatin which is the effector of change. Heterochromatin Protein 1 (HP1) members dynamically sculpt this change to and are thought to bring about heritable (cell-to-cell) changes in gene expressibility that can encompass large stretches of the genome. Aside from silencing structural genes, HP1 proteins are potentially more important for silencing repeats, including Transposable Elements (TEs) and Endogenous Retroviruses (ERVs), whose de-repression is associated with a variety of neuropsychiatric and neurodegenerative pathologies. Here we outline our plans to understand, in concrete molecular and cellular terms, the mechanism(s) by which mammalian HP1 proteins contribute to the normal development and function of the cerebral cortex. Our preliminary work has uncovered several interesting phenotypes in HP1 mutants that may model accelerated aging. Animals deficient for HP1beta and HP1gamma in the neocortex show deficits in spatial learning and display malformations of the dentate gyrus and cerebral cortex. Simultaneously, these animals display derepression of endogenous retroviruses in post-mitotic neurons of the cortex and especially hippocampus, implicating HP1 proteins as essential for retroviral silencing in neurons. To understand these phenomena we propose a full spectrum characterization of HP1 single and double mutants. This involves structural characterization, network and synapse analysis, in addition to a determination of retrotransposon activity and how this may lead to chimeric and aberrant gene transcription as measured by RNAseq. As a consensus of age-related changes to the epigenome emerges, a consistent observation is that loss of heterochromatin precedes the expression of repetitive elements1. Our proposed study of HP1–deficient neurons in the hippocampus aims to provide valuable insights into both the molecular underpinnings and the behavioral consequences of precocious epigenome dysregulation.