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Cell Rep. 2017 Apr 25;19(4):671-679. doi: 10.1016/j.celrep.2017.04.001.

KAT-Independent Gene Regulation by Tip60 Promotes ESC Self-Renewal but Not Pluripotency.

Author information

1
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Division of Genes and Development, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: thomas.fazzio@umassmed.edu.

Abstract

Although histone-modifying enzymes are generally assumed to function in a manner dependent on their enzymatic activities, this assumption remains untested for many factors. Here, we show that the Tip60 (Kat5) lysine acetyltransferase (KAT), which is essential for embryonic stem cell (ESC) self-renewal and pre-implantation development, performs these functions independently of its KAT activity. Unlike ESCs depleted of Tip60, KAT-deficient ESCs exhibited minimal alterations in gene expression, chromatin accessibility at Tip60 binding sites, and self-renewal, thus demonstrating a critical KAT-independent role of Tip60 in ESC maintenance. In contrast, KAT-deficient ESCs exhibited impaired differentiation into mesoderm and endoderm, demonstrating a KAT-dependent function in differentiation. Consistent with this phenotype, KAT-deficient mouse embryos exhibited post-implantation developmental defects. These findings establish separable KAT-dependent and KAT-independent functions of Tip60 in ESCs and during differentiation, revealing a complex repertoire of regulatory functions for this essential chromatin remodeling complex.

KEYWORDS:

Ep400; Kat5; Tip60; acetyltransferase; chromatin; development; differentiation; embryonic stem cells; self-renewal

PMID:
28445719
PMCID:
PMC5484067
DOI:
10.1016/j.celrep.2017.04.001
[Indexed for MEDLINE]
Free PMC Article

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