View Program - 63rd Annual Drosophila Research Conference

Large portions of eukaryotic genomes contain repetitive sequences that include transposable elements, which can be mobilized to generate new integrations in the host genome, therefore affecting genome function, stability and evolution. Germ cells possess the Piwi-interacting RNA (piRNA) pathway to repress transposable elements to maintain genome stability across generations. Whereas, uncontrolled transposable element expression in somatic cells causes mutations that do not get passed on to future generations but may lead to pathological consequences. We have uncovered that loss of function of a single zygotic gene, Hinfp, which encodes a conserved zinc finger transcription factor, is sufficient to cause de-repression of most transposable elements, resulting in a substantial DNA damage in somatic tissues. Deep sequencing, mutant clonal analyses and cell type specific RNAi experiments reveal that the key cell-autonomous target of Hinfp in this process is the linker histone Histone1, which has important roles in heterochromatin chromatin formation and transposable element repression. Pharmacological inhibition of reverse transcriptase by a combination of 3TC and AZT resulted in rescue of DNA damage in gut enterocytes. Moreover, transgenic expression of Hinfp or Histone1, but not Histone4 of core nucleosome, was sufficient to rescue the defects in repressing transposable elements and host genes. We also demonstrated that down regulation of Hinfp caused neurological defects in aging flies and enhanced the Ras oncoprotein-induced lethality and tissue growth. Overall, our findings suggest that Hinfp acts as a pivotal physiological regulator of Histone1- dependent silencing of most transposable elements, as well as many Drosophila genes, and serves as a new venue for studying genome stability, cancer progression, neurodegeneration and aging.

Hinfp is a guardian of the somatic genome by repressing transposable elements