TDP-43 safeguards the embryo genome from L1 retrotransposition

Ten D. Li, Kensaku Murano, Tomohiro Kitano, Youjia Guo, Lumi Negishi, Haruhiko Siomi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Transposable elements (TEs) are genomic parasites that propagate within the host genome and introduce mutations. Long interspersed nuclear element-1 (LINE-1 or L1) is the major TE class, which occupies nearly 20% of the mouse genome. L1 is highly active in mammalian preimplantation embryos, posing a major threat to genome integrity, but the mechanism of stage-specific protection against L1 retrotransposition is unknown. Here, we show that TAR DNA–binding protein 43 (TDP-43), mutations in which constitute a major risk factor for amyotrophic lateral sclerosis, inhibits L1 retrotransposition in mouse embryonic stem cells (mESCs) and preimplantation embryos. Knockdown of TDP-43 resulted in massive genomic L1 expansion and impaired cell growth in preimplantation embryos and ESCs. Functional analysis demonstrated that TDP-43 interacts with L1 open reading frame 1 protein (L1 ORF1p) to mediate genomic protection, and loss of this interaction led to derepression of L1 retrotransposition. Our results identify TDP-43 as a guardian of the embryonic genome.

Original languageEnglish
Article numbereabq3806
JournalScience Advances
Volume8
Issue number47
DOIs
Publication statusPublished - 2022 Nov 25

ASJC Scopus subject areas

  • General

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