Lsh regulates LTR retrotransposon repression independently of Dnmt3b function

Donncha S. Dunican, Hazel A. Cruickshanks, Masako Suzuki, Colin A. Semple, Tracey Davey, Robert J. Arceci, John M. Greally, Ian R. Adams, Richard R. Meehan

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: DNA methylation contributes to genomic integrity by suppressing repeat-associated transposition. In addition to the canonical DNA methyltransferases, several auxiliary chromatin factors are required to maintain DNA methylation at intergenic and satellite repeats. The interaction between Lsh, a chromatin helicase, and the de novo methyltransferase Dnmt3b facilitates deposition of DNA methylation at stem cell genes, which are hypomethylated in Lsh-/- embryos. We wished to determine if a similar targeting mechanism operates to maintain DNA methylation at repetitive sequences. Results: We mapped genome-wide DNA methylation patterns in Lsh-/- and Dnmt3b-/- somatic cells. DNA methylation is predominantly lost from specific genomic repeats in Lsh-/- cells: LTR -retrotransposons, LINE-1 repeats and mouse satellites. RNA-seq experiments demonstrate that specific IAP LTRs and satellites, but not LINE-1 elements, are aberrantly transcribed in Lsh-/- cells. LTR hypomethylation in Dnmt3b-/- cells is moderate, whereas IAP, LINE-1 and satellite elements are hypomethylated but silent. Repressed LINE-1 elements in Lsh-/- cells gain H3K4me3, but H3K9me3 levels are unaltered, indicating that DNA hypomethylation alone is not permissive for their transcriptional activation. Mis-expressed IAPs and satellites lose H3K9me3 and gain H3K4me3 in Lsh-/- cells. Conclusions: Our study emphasizes that regulation of repetitive elements by Lsh and DNA methylation is selective and context dependent. Silencing of repeats in somatic cells appears not to be critically dependent on Dnmt3b function. We propose a model where Lsh is specifically required at a precise developmental window to target de novo methylation to repeat sequences, which is subsequently maintained by Dnmt1 to enforce selective repeat silencing.

Original languageEnglish (US)
Article numberR146
JournalGenome Biology
Volume14
Issue number12
DOIs
StatePublished - 2013

Fingerprint

Retroelements
retrotransposons
DNA methylation
DNA Methylation
methylation
Long Interspersed Nucleotide Elements
DNA
methyltransferases
Methyltransferases
somatic cells
Chromatin
cells
chromatin
genomics
repetitive sequences
transposition (genetics)
Nucleic Acid Repetitive Sequences
transcriptional activation
repression
Methylation

ASJC Scopus subject areas

  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Medicine(all)

Cite this

Dunican, D. S., Cruickshanks, H. A., Suzuki, M., Semple, C. A., Davey, T., Arceci, R. J., ... Meehan, R. R. (2013). Lsh regulates LTR retrotransposon repression independently of Dnmt3b function. Genome Biology, 14(12), [R146]. https://doi.org/10.1186/gb-2013-14-12-r146

Lsh regulates LTR retrotransposon repression independently of Dnmt3b function. / Dunican, Donncha S.; Cruickshanks, Hazel A.; Suzuki, Masako; Semple, Colin A.; Davey, Tracey; Arceci, Robert J.; Greally, John M.; Adams, Ian R.; Meehan, Richard R.

In: Genome Biology, Vol. 14, No. 12, R146, 2013.

Research output: Contribution to journalArticle

Dunican, DS, Cruickshanks, HA, Suzuki, M, Semple, CA, Davey, T, Arceci, RJ, Greally, JM, Adams, IR & Meehan, RR 2013, 'Lsh regulates LTR retrotransposon repression independently of Dnmt3b function', Genome Biology, vol. 14, no. 12, R146. https://doi.org/10.1186/gb-2013-14-12-r146
Dunican, Donncha S. ; Cruickshanks, Hazel A. ; Suzuki, Masako ; Semple, Colin A. ; Davey, Tracey ; Arceci, Robert J. ; Greally, John M. ; Adams, Ian R. ; Meehan, Richard R. / Lsh regulates LTR retrotransposon repression independently of Dnmt3b function. In: Genome Biology. 2013 ; Vol. 14, No. 12.
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abstract = "Background: DNA methylation contributes to genomic integrity by suppressing repeat-associated transposition. In addition to the canonical DNA methyltransferases, several auxiliary chromatin factors are required to maintain DNA methylation at intergenic and satellite repeats. The interaction between Lsh, a chromatin helicase, and the de novo methyltransferase Dnmt3b facilitates deposition of DNA methylation at stem cell genes, which are hypomethylated in Lsh-/- embryos. We wished to determine if a similar targeting mechanism operates to maintain DNA methylation at repetitive sequences. Results: We mapped genome-wide DNA methylation patterns in Lsh-/- and Dnmt3b-/- somatic cells. DNA methylation is predominantly lost from specific genomic repeats in Lsh-/- cells: LTR -retrotransposons, LINE-1 repeats and mouse satellites. RNA-seq experiments demonstrate that specific IAP LTRs and satellites, but not LINE-1 elements, are aberrantly transcribed in Lsh-/- cells. LTR hypomethylation in Dnmt3b-/- cells is moderate, whereas IAP, LINE-1 and satellite elements are hypomethylated but silent. Repressed LINE-1 elements in Lsh-/- cells gain H3K4me3, but H3K9me3 levels are unaltered, indicating that DNA hypomethylation alone is not permissive for their transcriptional activation. Mis-expressed IAPs and satellites lose H3K9me3 and gain H3K4me3 in Lsh-/- cells. Conclusions: Our study emphasizes that regulation of repetitive elements by Lsh and DNA methylation is selective and context dependent. Silencing of repeats in somatic cells appears not to be critically dependent on Dnmt3b function. We propose a model where Lsh is specifically required at a precise developmental window to target de novo methylation to repeat sequences, which is subsequently maintained by Dnmt1 to enforce selective repeat silencing.",
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AB - Background: DNA methylation contributes to genomic integrity by suppressing repeat-associated transposition. In addition to the canonical DNA methyltransferases, several auxiliary chromatin factors are required to maintain DNA methylation at intergenic and satellite repeats. The interaction between Lsh, a chromatin helicase, and the de novo methyltransferase Dnmt3b facilitates deposition of DNA methylation at stem cell genes, which are hypomethylated in Lsh-/- embryos. We wished to determine if a similar targeting mechanism operates to maintain DNA methylation at repetitive sequences. Results: We mapped genome-wide DNA methylation patterns in Lsh-/- and Dnmt3b-/- somatic cells. DNA methylation is predominantly lost from specific genomic repeats in Lsh-/- cells: LTR -retrotransposons, LINE-1 repeats and mouse satellites. RNA-seq experiments demonstrate that specific IAP LTRs and satellites, but not LINE-1 elements, are aberrantly transcribed in Lsh-/- cells. LTR hypomethylation in Dnmt3b-/- cells is moderate, whereas IAP, LINE-1 and satellite elements are hypomethylated but silent. Repressed LINE-1 elements in Lsh-/- cells gain H3K4me3, but H3K9me3 levels are unaltered, indicating that DNA hypomethylation alone is not permissive for their transcriptional activation. Mis-expressed IAPs and satellites lose H3K9me3 and gain H3K4me3 in Lsh-/- cells. Conclusions: Our study emphasizes that regulation of repetitive elements by Lsh and DNA methylation is selective and context dependent. Silencing of repeats in somatic cells appears not to be critically dependent on Dnmt3b function. We propose a model where Lsh is specifically required at a precise developmental window to target de novo methylation to repeat sequences, which is subsequently maintained by Dnmt1 to enforce selective repeat silencing.

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