Argonaute NRDE-3 and MBT domain protein LIN-61 redundantly recruit an H3K9me3 HMT to prevent embryonic lethality and transposon expression

Genes Dev. 2021 Jan 1;35(1-2):82-101. doi: 10.1101/gad.344234.120. Epub 2020 Dec 10.

Abstract

The establishment and maintenance of chromatin domains shape the epigenetic memory of a cell, with the methylation of histone H3 lysine 9 (H3K9me) defining transcriptionally silent heterochromatin. We show here that the C. elegans SET-25 (SUV39/G9a) histone methyltransferase (HMT), which catalyzes H3K9me1, me2 and me3, can establish repressed chromatin domains de novo, unlike the SETDB1 homolog MET-2. Thus, SET-25 is needed to silence novel insertions of RNA or DNA transposons, and repress tissue-specific genes de novo during development. We identify two partially redundant pathways that recruit SET-25 to its targets. One pathway requires LIN-61 (L3MBTL2), which uses its four MBT domains to bind the H3K9me2 deposited by MET-2. The second pathway functions independently of MET-2 and involves the somatic Argonaute NRDE-3 and small RNAs. This pathway targets primarily highly conserved RNA and DNA transposons. These redundant SET-25 targeting pathways (MET-2-LIN-61-SET-25 and NRDE-3-SET-25) ensure repression of intact transposons and de novo insertions, while MET-2 can act alone to repress simple and satellite repeats. Removal of both pathways in the met-2;nrde-3 double mutant leads to the loss of somatic H3K9me2 and me3 and the synergistic derepression of transposons in embryos, strongly elevating embryonic lethality.

Keywords: Argonaute; HMT; LIN-61; MBT domain proteins; MET-2; NRDE-3; SET-25; heterochromatin; histone methyltransferases (HMTs); transposon silencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Transposable Elements / genetics*
  • Embryo, Nonmammalian
  • Gene Expression Regulation / genetics*
  • Gene Silencing
  • Heterochromatin / genetics*
  • Heterochromatin / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Methylation
  • Mutation
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA Transposable Elements
  • Heterochromatin
  • Histones
  • LIN-61 protein, C elegans
  • NRDE-3 protein, C elegans
  • RNA-Binding Proteins
  • Histone-Lysine N-Methyltransferase
  • Met-2 protein, C elegans
  • SET-25 protein, C elegans