Homozygous disruption of the <i>tip60</i> gene causes early embryonic lethality

Hu, Yaofei; Fisher, Joseph B.; Koprowski, Stacy; McAllister, Donna; Kim, Minsu; Lough, John

doi:10.1002/dvdy.22110

Cited by 110 publications

(117 citation statements)

References 42 publications

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“…Since embryonic development is dependent on the precise regulation of temporal-spatial patterns of gene expression, establishing the correct pattern of histone acetylation at developmentally important gene loci is critical. Accordingly, MOF and MOZ, as well two other MYST family members, QKF (MORF/MYST4/KAT6B) and TIP60 (KAT5), have distinct and essential functions during mammalian development (21,24,34,47,63,64,67,69). We show here that the MYST histone acetyltransferase HBO1 is required for the expression of a broad range of genes and is essential for the acetylation of H3K14.…”

mentioning

confidence: 70%

HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development

Kueh

Dixon

Voss

et al. 2011

Molecular and Cellular Biology

151

182

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We report here that the MYST histone acetyltransferase HBO1 (histone acetyltransferase bound to ORC; MYST2/KAT7) is essential for postgastrulation mammalian development. Lack of HBO1 led to a more than 90% reduction of histone 3 lysine 14 (H3K14) acetylation, whereas no reduction of acetylation was detected at other histone residues. The decrease in H3K14 acetylation was accompanied by a decrease in expression of the majority of genes studied. However, some genes, in particular genes regulating embryonic patterning, were more severely affected than "housekeeping" genes. Development of HBO1-deficient embryos was arrested at the 10-somite stage. Blood vessels, mesenchyme, and somites were disorganized. In contrast to previous studies that reported cell cycle arrest in HBO1-depleted cultured cells, no defects in DNA replication or cell proliferation were seen in Hbo1 mutant embryo primary fibroblasts or immortalized fibroblasts. Rather, a high rate of cell death and DNA fragmentation was observed in Hbo1 mutant embryos, resulting initially in the degeneration of mesenchymal tissues and ultimately in embryonic lethality. In conclusion, the primary role of HBO1 in development is that of a transcriptional activator, which is indispensable for H3K14 acetylation and for the normal expression of essential genes regulating embryonic development.In general, acetylation of histone lysine residues correlates positively and strongly with transcriptionally active regions of the genome (37, 49, 54); in contrast, heterochromatin is hypoacetylated (7,8). It has been proposed that particular patterns of posttranslational histone modifications represent a "code" and that histone modifications are recognized by transcription factors via specific chromatin-binding domains (2,31,60,68). Indeed, acetylated lysines are recognized by bromodomains (13, 30). However, histones can be acetylated at multiple sites, and with few exceptions, very little is known about the biological function of acetylation at specific histone lysine residues in multicellular organisms. Moreover, the residue specificity of few histone acetyltransferases has been characterized in vertebrate organisms. Two members of the MYST family of histone acetyltransferases, MOF (MYST1/KAT8) and MOZ (MYST3/ KAT6A), have highly restricted substrate specificities in vivo.In Drosophila melanogaster and mice in vivo, as well as in human cells in vitro, MOF is specifically required for acetylation of histone 4 lysine 16 (H4K16) (3, 61, 64), whereas MOZ has a specific role in the acetylation of H3K9 in Hox gene clusters (69). Since embryonic development is dependent on the precise regulation of temporal-spatial patterns of gene expression, establishing the correct pattern of histone acetylation at developmentally important gene loci is critical. Accordingly, MOF and MOZ, as well two other MYST family members, QKF (MORF/MYST4/KAT6B) and TIP60 (KAT5), have distinct and essential functions during mammalian development (21,24,34,47,63,64,67,69). We show here that the MYST histone acety...

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mentioning

confidence: 70%

HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development

Kueh

Dixon

Voss

et al. 2011

Molecular and Cellular Biology

151

182

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“…This result is consistent with the finding that a Tip60 knockout mouse line. 19) Chromodomains are specialized binding modules that contain conserved hydrophobic amino acids, which interact with the methyl groups on methylated lysine residues. 20,21) For example, the chromodomain in HP1α interacts with H3K9me3.…”

Section: Discussionmentioning

confidence: 99%

The chromodomain-containing histone acetyltransferase TIP60 acts as a code reader, recognizing the epigenetic codes for initiating transcription

Kim

Jang

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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TIP60 can act as a transcriptional activator or a repressor depending on the cellular context. However, little is known about the role of the chromodomain in the functional regulation of TIP60. In this study, we found that TIP60 interacted with H3K4me3 in response to TNF-α signaling. TIP60 bound to H3K4me3 at the promoters of the NF-κB target genes IL6 and IL8. Unlike the wild-type protein, a TIP60 chromodomain mutant did not localize to chromatin regions. Because TIP60 binds to histones with specific modifications and transcriptional regulators, we used a histone peptide assay to identify histone codes recognized by TIP60. TIP60 preferentially interacted with methylated or acetylated histone H3 and H4 peptides. Phosphorylation near a lysine residue significantly reduced the affinity of TIP60 for the modified histone peptides. Our findings suggest that TIP60 acts as a functional link between the histone code and transcriptional regulators.

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“…These two proteins are broadly expressed, fulfil multiple roles in fundamental cellular processes and are both essential for embryonic development in mice 11,12,29 . Our data show that USP7 is an essential DUB in adipogenesis and reveal the underlying mechanisms to be deubiquitination and stabilization of Tip60.…”

Section: Discussionmentioning

confidence: 99%

“…The Tip60 complex can also modify chromatin around DNA doublestranded breaks to support repair, demonstrating an additional important cellular function 10 . Its role in these two fundamental cellular processes may explain the embryonic lethality observed in Tip60 knockout mice 11,12 and early pupal lethality after Tip60 depletion in Drosophila melanogaster 13 . Similar to SRC-3, Tip60 can undergo multiple PTM, including phosphorylation 14 , sumoylation 15 and ubiquitination 16 .…”

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confidence: 99%

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

et al. 2013

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Transcriptional coregulators, including the acetyltransferase Tip60, have a key role in complex cellular processes such as differentiation. Whereas post-translational modifications have emerged as an important mechanism to regulate transcriptional coregulator activity, the identification of the corresponding demodifying enzymes has remained elusive. Here we show that the expression of the Tip60 protein, which is essential for adipocyte differentiation, is regulated through polyubiquitination on multiple residues. USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels. Furthermore, inhibition of USP7 expression and activity decreases adipogenesis. Transcriptome analysis reveals several cell cycle genes to be co-regulated by both Tip60 and USP7. Knockdown of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis.

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Homozygous disruption of the tip60 gene causes early embryonic lethality

Cited by 110 publications

References 42 publications

HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development

HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development

The chromodomain-containing histone acetyltransferase TIP60 acts as a code reader, recognizing the epigenetic codes for initiating transcription

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

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