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Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
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Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
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Journal Article
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET
2010
Overview
Stem cell proviral silencing
Endogenous retroviruses are widely dispersed in mammalian genomes, and are silenced in somatic cells by DNA methylation. Here, an endogenous retroviruses silencing pathway independent of DNA methylation is shown to operate in embryonic stem cells. The pathway involves the histone H3K9 methyltransferase ESET/SETDB1 and might be important for endogenous retrovirus silencing during the stages in embryogenesis when DNA methylation is reprogrammed.
Endogenous retroviruses (ERVs) are widely dispersed in mammalian genomes, and are silenced in somatic cells by DNA methylation. Here, an ERV silencing pathway independent of DNA methylation is shown to operate in embryonic stem cells. The pathway involves the histone H3K9 methyltransferase ESET and might be important for ERV silencing during the stages in embryogenesis when DNA methylation is reprogrammed.
Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising ∼10% of the mouse genome
1
. These parasitic elements are responsible for >10% of spontaneous mutations
2
. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells
3
,
4
,
5
, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV)
6
,
7
,
8
. Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts
9
. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Krüppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28)
10
,
11
are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (
Dnmt1
-/-
Dnmt3a
-/-
Dnmt3b
-/-
) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Biological and medical sciences
/ Control
/ DNA
/ DNA (Cytosine-5-)-Methyltransferase 1
/ DNA (Cytosine-5-)-Methyltransferases - deficiency
/ DNA (Cytosine-5-)-Methyltransferases - genetics
/ DNA (Cytosine-5-)-Methyltransferases - metabolism
/ Embryonic Stem Cells - enzymology
/ Embryonic Stem Cells - metabolism
/ Embryonic Stem Cells - virology
/ Endogenous Retroviruses - genetics
/ Fundamental and applied biological sciences. Psychology
/ Histone-Lysine N-Methyltransferase - deficiency
/ Histone-Lysine N-Methyltransferase - genetics
/ Histone-Lysine N-Methyltransferase - metabolism
/ Humanities and Social Sciences
/ letter
/ Mice
/ Molecular and cellular biology
/ Nuclear Proteins - metabolism
/ Protein Methyltransferases - deficiency
/ Protein Methyltransferases - genetics
/ Protein Methyltransferases - metabolism
/ Proteins
/ Repressor Proteins - metabolism
/ Science
