Title

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

UMMS Affiliation

Program in Molecular Medicine; Department of Molecular, Cell, and Cancer Biology; Graduate School of Biomedical Sciences

Publication Date

2021-10-12

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Genetics and Genomics | Nucleic Acids, Nucleotides, and Nucleosides | Translational Medical Research

Abstract

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.

Keywords

Drosophila, Hinfp, genome stability, somatic, transposable elements, UMCCTS funding

DOI of Published Version

10.1073/pnas.2100839118

Source

Nirala NK, Li Q, Ghule PN, Chen HJ, Li R, Zhu LJ, Wang R, Rice NP, Mao J, Stein JL, Stein GS, van Wijnen AJ, Ip YT. Hinfp is a guardian of the somatic genome by repressing transposable elements. Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2100839118. doi: 10.1073/pnas.2100839118. PMID: 34620709; PMCID: PMC8521681. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

34620709

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