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kat7

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Official Full Name
K(lysine) acetyltransferase 7
Background
Component of the HBO1 complex which has a histone H4-specific acetyltransferase activity, a reduced activity toward histone H3 and is responsible for the bulk of histone H4 acetylation in vivo. Through chromatin acetylation it may regulate DNA replication and act as a coactivator of TP53-dependent transcription. Specifically represses AR-mediated transcription.
Synonyms
KAT7; K(lysine) acetyltransferase 7; HBO1; HBOA; MYST2; ZC2HC7; histone acetyltransferase KAT7; MYST-2; lysine acetyltransferase 7; histone acetyltransferase MYST2; MYST histone acetyltransferase 2; MOZ, YBF2/SAS3, SAS2 and TIP60 protein 2; histone acetyltransferase binding to ORC1; HBO1, HBOA, MYST2, ZC2HC7

Recent Research

KAT7 (also known as HBO1 or MYST2), a member of the MYST KAT family, is an H4-specific histone acetylase acting as an essential catalytic subunit of the histone H4 acetyltransferase complex. Generally, KAT7 is enriched near the transcriptional starting site of active genes and results in specific acetylation on histone H4 to unfold chromatin so that the DNA can be accessed, and then be replicated or transcribed.

Histone acetylation has an important role in DNA replication, gene regulation and repair. Some reports have shown that KAT7 is involved in the regulation of thymopoiesis and has a critical role in the regulation of conventional and innate-like T cell development. KAT7-deficient mice displayed relatively normal thymic development. Besides, KAT7 has been shown to be involved in a number of replication-associated processes via interactions with replication factors. Studies that have depleted KAT7 in cell lines have observed stalled DNA replication, suggesting that inactivation of KAT7 would result in a similar outcome.

The centromere is a specific chromatin site of eukaryotic chromosomes containing a conserved histone H3 variant: CENP-A. CENP-A is a crucial component for the maintenance of centromere chromatin identity. It has been shown that the histone acetyltransferase KAT7 positively regulates centromeric CENP-A assembly KAT7 localized at endogenous centromeres in G1 phase, and knocking out KAT7 reduced centromeric CENP-A assembly. A combination of knocking out KAT7 and overproducing Suv39h1 synthetically perturbed chromosomal segregation, leading to increased micronucleus formation. Furthermore, KAT7 tethered to a heterochromatinized alphoidtetO site reduced H3K9me3 modifications and provided competence for new histone H3.3 or CENP-A assembly.KAT7 regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation.

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving multiple cellular participants, of which synovial fibroblasts (SFs) are tightly connected with the development and progression of RA. KAT7 is up-regulated in SFs of RA patients, which is attributed to the stimulation by RA-associated proinflammatory cytokines, such as TNF-a, IL-1b or IFN-g. The supernatants of SFs over-expressing KAT7 promotes T helper 17 (Th17) cell differentiation, due to increased production and secretion of IL-6 and TGF-b induced by KAT7 over-expression, which is accomplished by their transcriptional activation via KAT7- mediated epigenetic mechanism. Moreover, KAT7 promotes Th17 cell migration via inducing CCL20 production in SFs through activating p44/42 MAPK pathway.

In addition, KAT7 deficient mice are embryonic lethal at E10.5 due to defects in post-gastrulation mammalian development that disrupted somites, mesenchyme, and possibly blood vessel formation. It has been shown that histone acetylation is important for EC- enriched gene expression and that KAT7 plays a significant role in endothelial function, in part, by regulating intragenic histone acetylation at VEGFR-2.KAT7 localized to the VEGFR-2 locus and in vitro KAT7 depletion in human ECs perturbed endothelial cell (EC) gene expression, including VEGFR-2. The reduced VEGFR-2 expression level in KAT7-depleted EC was mediated transcriptionally by reducing AcH4, AcH3K14, and Pol II occupancy in the VEGFR-2 intragenic region. Perturbed EC gene expression in KAT7-depleted ECs was associated with deficient EC function. Importantly, KAT7 morpholino (MO) inhibition in zebrafish embryos (3 dpf) resulted in aberrant vessel formation with compromised circulatory integrity, especially hemorrhage, which could be rescued by human KAT7 RNA. Furthermore, these zebrafish embryos showed reduced expression of EC-enriched genes that were similarly perturbed in human KAT7-depleted ECs. Expression of a KAT7-regulated gene, the VEGFR-2 homolog KDRL, in KAT7-depleted zebrafish salvaged aberrant vessel formation and partly restored the disrupted circulatory integrity in these zebrafish.

References:

  1. Newman D M, et al. Essential role for the histone acetyltransferase KAT7 in T cell development, fitness, and survival. Journal of Leukocyte Biology, 2016, 101(4).
  2. Gao S, et al. Upregulated KAT7 in synovial fibroblasts promotes Th17 cell differentiation and infiltration in rheumatoid arthritis. Biochemical & Biophysical Research Communications, 2017, 489(2).
  3. Ohzeki J, et al. KAT7/HBO1/MYST2 Regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation. Developmental Cell, 2016, 37(5):413-427.
  4. Yan M S, et al. Histone acetyltransferase 7 (KAT7)-dependent intragenic histone acetylation regulates endothelial cell gene regulation. Journal of Biological Chemistry, 2018, 293(12):jbc.RA117.001383.