Hinfp is a guardian of the somatic genome by repressing transposable elements – pnas.org

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Edited by Hugo Bellen, Baylor College of Medicine, Houston, TX, and approved September 3, 2021 (received for review January 14, 2021)
Repression of the large number of transposable elements in eukaryotic genomes is essential for genome stability. The Piwi-interacting RNA and short interfering RNA pathways are critical for repressing transposable elements in germlines, but the repression of transposable elements in somatic tissues involves other components. While the mammalian Hinfp has been shown to regulate Histone4 and cell-cycle progression, our manuscript provides evidence that a function of the Drosophila Hinfp is to maintain Histone1 expression to repress most transposable elements in somatic genomes. This Hinfp–Histone1 axis provides a venue to study maintenance of genome stability and progression of pathological outcomes.
Germ cells possess the Piwi-interacting RNA pathway to repress transposable elements and maintain genome stability across generations. Transposable element mobilization in somatic cells does not affect future generations, but nonetheless can lead to pathological outcomes in host tissues. We show here that loss of function of the conserved zinc-finger transcription factor Hinfp causes dysregulation of many host genes and derepression of most transposable elements. There is also substantial DNA damage in somatic tissues of Drosophila after loss of Hinfp. Interference of transposable element mobilization by reverse-transcriptase inhibitors can suppress some of the DNA damage phenotypes. The key cell-autonomous target of Hinfp in this process is Histone1, which encodes linker histones essential for higher-order chromatin assembly. Transgenic expression of Hinfp or Histone1, but not Histone4 of core nucleosome, is sufficient to rescue the defects in repressing transposable elements and host genes. Loss of Hinfp enhances Ras-induced tissue growth and aging-related phenotypes. Therefore, Hinfp is a physiological regulator of Histone1-dependent silencing of most transposable elements, as well as many host genes, and serves as a venue for studying genome instability, cancer progression, neurodegeneration, and aging.
Author contributions: N.K.N., J.M., J.L.S., G.S.S., A.J.v.W., and Y.T.I. designed research; N.K.N., Q.L., P.N.G., H.-J.C., and Y.T.I. performed research; N.K.N., Q.L., P.N.G., H.-J.C., R.L., L.J.Z., R.W., N.P.R., J.M., J.L.S., G.S.S., A.J.v.W., and Y.T.I. analyzed data; and N.K.N., R.L., L.J.Z., R.W., J.L.S., G.S.S., A.J.v.W., and Y.T.I. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2100839118/-/DCSupplemental.
All study data are included in the article and/or SI Appendix. Data are original and have been deposited in the GEO database (GEO accession no. GSE138430) (71), and supplementary Tables 1 and 2 for Histone and heterochromatic gene expression dataset Excel tables are available in FigShare (https://doi.org/10.6084/m9.figshare.15506415.v1) (72).
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