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Epigenetics Chromatin. 2017 Feb 23;10:8. doi: 10.1186/s13072-017-0115-7. eCollection 2017.

SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation.

Author information

1
Department of Oncology, Wayne State University School of Medicine, Detroit, MI USA.
2
Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI USA.
3
Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.

Abstract

BACKGROUND:

Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone 4 lysine 20 (H4K20me3) in pluripotency and development are largely unknown.

RESULTS:

Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5-bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and perturbed differentiation of SMYD5-depleted ES cells.

CONCLUSIONS:

Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin.

KEYWORDS:

ChIP-Seq; Chromatin; Differentiation; Embryoid body; Embryonic stem cells; Epigenetics; Gene expression; Genomics; H4K20me3; Heterochromatin; Histone methyltransferase; LINE; LTR; Pluripotent; RNA-Seq; Repetitive DNA; SMYD5; Self-renewal

PMID:
28250819
PMCID:
PMC5324308
DOI:
10.1186/s13072-017-0115-7
[Indexed for MEDLINE]
Free PMC Article

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