Roles of Zinc-Finger Transcription Factor Jim in Metabolism and Gene Regulation

Aging is characterized by complex remodeling of the epigenome, including loss of repressive heterochromatin that may subsequently lead to aberrant gene expression and de-repression of retrotransposons (RTE). However, how specific perturbations to heterochromatin affect the aging process are not fully understood. Using the model system Drosophila melanogaster (fruit flies), we identified the transcription factor "Jim" in for a genetic screen for genes that are necessary for RTE silencing. We found that reducing Jim expression enhances RTE mobilization in an RTE reporter line. Jim overexpression increases silencing in a heterochromatin reporter line and increases levels H3K9me2 levels, a histone modification associated with heterochromatin. Whole-body Jim overexpression dramatically shortens lifespan while increasing starvation resistance in male flies. Oenocyte (analogous to liver)-specific Jim overexpression also shortens lifespan and produces major deficits in desiccation resistance and cuticle waterproofing. Jim overexpression led to differential expression of several thousand target genes, which were enriched for genes involved in lipid and carbohydrate metabolism. We found that Jim knockout or knockdown during development is lethal and adult-specific knockdown radically shortens lifespan in both sexes.  We conclude that Jim is a major regulator of heterochromatic silencing, metabolism, and lifespan.