更新于：2024-05-01

KAT7

lysine acetyltransferase 7

更新于：2024-05-01

基本信息

别名

HBO1、HBOa、Histone acetyltransferase binding to ORC1

+ [9]

简介

Catalytic subunit of histone acetyltransferase HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby regulating various processes, such as gene transcription, protein ubiquitination, immune regulation, stem cell pluripotent and self-renewal maintenance and embryonic development (PubMed:16387653, PubMed:21753189, PubMed:24065767, PubMed:26620551, PubMed:31767635, PubMed:31827282). Some complexes also catalyze acetylation of histone H4 at 'Lys-5', 'Lys-8' and 'Lys-12' (H4K5ac, H4K8ac and H4K12ac, respectively), regulating DNA replication initiation, regulating DNA replication initiation (PubMed:10438470, PubMed:19187766, PubMed:20129055, PubMed:24065767). Specificity of the HBO1 complexes is determined by the scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE (JADE1, JADE2 and JADE3) scaffold direct KAT7/HBO1 specificity towards histone H4 (PubMed:19187766, PubMed:20129055, PubMed:24065767, PubMed:26620551). H3K14ac promotes transcriptional elongation by facilitating the processivity of RNA polymerase II (PubMed:31827282). Acts as a key regulator of hematopoiesis by forming a complex with BRD1/BRPF2, directing KAT7/HBO1 specificity towards H3K14ac and promoting erythroid differentiation (PubMed:21753189). H3K14ac is also required for T-cell development (By similarity). KAT7/HBO1-mediated acetylation facilitates two consecutive steps, licensing and activation, in DNA replication initiation: H3K14ac facilitates the activation of replication origins, and histone H4 acetylation (H4K5ac, H4K8ac and H4K12ac) facilitates chromatin loading of MCM complexes, promoting DNA replication licensing (PubMed:10438470, PubMed:11278932, PubMed:18832067, PubMed:19187766, PubMed:20129055, PubMed:21856198, PubMed:24065767, PubMed:26620551). Acts as a positive regulator of centromeric CENPA assembly: recruited to centromeres and mediates histone acetylation, thereby preventing centromere inactivation mediated by SUV39H1, possibly by increasing histone turnover/exchange (PubMed:27270040). Involved in nucleotide excision repair: phosphorylation by ATR in response to ultraviolet irradiation promotes its localization to DNA damage sites, where it mediates histone acetylation to facilitate recruitment of XPC at the damaged DNA sites (PubMed:28719581). Acts as an inhibitor of NF-kappa-B independently of its histone acetyltransferase activity (PubMed:16997280). Plays a central role in the maintenance of leukemia stem cells in acute myeloid leukemia (AML) (PubMed:31827282). Acts by mediating acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby facilitating the processivity of RNA polymerase II to maintain the high expression of key genes, such as HOXA9 and HOXA10 that help to sustain the functional properties of leukemia stem cells (PubMed:31827282).

关联

项与 KAT7 相关的药物

WM-3835

靶点

KAT7

作用机制

KAT7抑制剂

在研机构-

原研机构

Peter MacCallum Cancer Institute

在研适应症-

非在研适应症

急性髓性白血病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 KAT7 相关的临床结果

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100 项与 KAT7 相关的转化医学

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0 项与 KAT7 相关的专利（医药）

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199

项与 KAT7 相关的文献（医药）

2024-03-01·NAR cancer

The ORFIUS complex regulates ORC2 localization at replication origins.

Article

作者: Zelei Yang ; Saie Mogre ; Ruiyang He ; Emma L Berdan ; Shannan J Ho Sui ; Sarah J Hill

High-grade serous ovarian cancer (HGSC) is a lethal malignancy with elevated replication stress (RS) levels and defective RS and RS-associated DNA damage responses. Here we demonstrate that the bromodomain-containing protein BRD1 is a RS suppressing protein that forms a replication origin regulatory complex with the histone acetyltransferase HBO1, the BRCA1 tumor suppressor, and BARD1, ORigin FIring Under Stress (ORFIUS). BRD1 and HBO1 promote eventual origin firing by supporting localization of the origin licensing protein ORC2 at origins. In the absence of BRD1 and/or HBO1, both origin firing and nuclei with ORC2 foci are reduced. BRCA1 regulates BRD1, HBO1, and ORC2 localization at replication origins. In the absence of BRCA1, both origin firing and nuclei with BRD1, HBO1, and ORC2 foci are increased. In normal and non-HGSC ovarian cancer cells, the ORFIUS complex responds to ATR and CDC7 origin regulatory signaling and disengages from origins during RS. In BRCA1-mutant and sporadic HGSC cells, BRD1, HBO1, and ORC2 remain associated with replication origins, and unresponsive to RS, DNA damage, or origin regulatory kinase inhibition. ORFIUS complex dysregulation may promote HGSC cell survival by allowing for upregulated origin firing and cell cycle progression despite accumulating DNA damage, and may be a RS target.

2024-01-25·Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association

Chromosomal copy number amplification-driven Linc01711 contributes to gastric cancer progression through histone modification-mediated reprogramming of cholesterol metabolism.

Article

作者: Ben Yue ; Jianjun Chen ; Tianshang Bao ; Yuanruohan Zhang ; Linxi Yang ; Zizhen Zhang ; Zheng Wang ; Chunchao Zhu

BACKGROUND:

Chromosome gains or localized amplifications are frequently observed in human gastric cancer (GC) and are major causes of aberrant oncogene activation. However, the significance of long non-coding RNAs (LncRNAs) in the above process is largely unknown.

METHODS:

The copy number aberrations (CNAs) data of GC samples were downloaded and analyzed from the TCGA database. qRT-PCR and fluorescence in situ hybridization were used to evaluate the expression of Linc01711 in GC. The effects of Linc01711 on GC progression were investigated through in vitro and in vivo assays. The mechanism of Linc01711 action was explored through transcriptome sequencing, chromatin immunoprecipitation sequencing, RNA immunoprecipitation, RNA pull-down and chromatin isolation by RNA purification (ChIRP) assays.

RESULTS:

We report for the first time a novel DNA copy number amplification-driven LncRNA on chromosome 20q13, designated Linc01711 in human GC, which is highly associated with malignant features. Functionally, Linc01711 significantly accelerates the proliferation and metastasis of GC. Mechanistically, Linc01711 acts as a modular scaffold to promote the binding of histone acetyltransferase HBO1 and histone demethylase KDM9. By coordinating the localization of the HBO1/KDM9 complex, Linc01711 specifies the histone modification pattern on the target genes, such as LPCAT1, and consequently facilitates the cholesterol synthesis, thereby contributing to tumor progression.

CONCLUSIONS:

Our findings suggest that copy number amplification-driven Linc01711 may serve as a promising prognostic predictor for GC patients and targeting Linc01711-related cholesterol metabolism pathway may be meaningful in anticancer strategies.

2023-11-27·International journal of biological macromolecules

MYST family histone acetyltransferases regulate reproductive diapause initiation.

Article

作者: Hao-Min An ; Yi-Fei Dai ; Jun Zhu ; Wen Liu ; Xiao-Ping Wang

Histone acetylation, a crucial epigenetic mechanism, has been suggested to play a role in diapause regulation, but this has not been confirmed through gene loss-of-function studies. In this work, we investigated the involvement of MYST family genes, which are key writers of histone acetylation, in initiating reproductive diapause using the cabbage beetle Colaphellus bowringi as a model. We identified C. bowringi orthologs of MYST, including Tip60, KAT6A, KAT7, and KAT8, from previous transcriptomes. Analyses of phylogenetic trees and protein domains indicated that these MYST proteins are structurally conserved across animal species. Expression of these MYST genes was found to be enriched in heads and ovaries of C. bowringi. Under reproductive photoperiod conditions, RNAi targeting MYST genes, especially KAT8, suppressed ovarian growth and yolk deposition, resembling the characteristics of diapausing ovaries. Additionally, KAT8 knockdown led to the upregulation of diapause-related genes, such as heat shock proteins and diapause protein 1, and the emergence of diapause-like guts. Moreover, KAT8 knockdown reduced the expression of a crucial enzyme involved in juvenile hormone (JH) biosynthesis, likely due to decreased H4K16ac levels. Consequently, our findings suggest that MYST family genes, specifically KAT8, influence the JH signal, thereby regulating the initiation of reproductive diapause.

项与 KAT7 相关的新闻（医药）

2023-07-10

·生物谷

Advanced Science：赵英明/黄河等揭示全新蛋白质修饰类型

细胞代谢为生命过程提供能量，同时，代谢物可共价修饰蛋白质来发挥信号传导功能。虽然许多代谢物在代谢通路中的作用广为人知，但它们介导细胞信号调控的功能有待探索。细胞代谢为生命过程提供能量，同时，代谢物可共价修饰蛋白质来发挥信号传导功能。虽然许多代谢物在代谢通路中的作用广为人知，但它们介导细胞信号调控的功能有待探索。酮体（包括丙酮、乙酰乙酸和β-羟基丁酸）为脂质代谢产物。在葡萄糖缺乏的状态下，肝脏产生的酮体可用作多种组织的替代能源，且与多种病理生理状态密切相关。芝加哥大学赵英明教授团队和中科院上海药物所黄河研究员课题组前期合作揭示了β-羟基丁酸驱动的赖氨酸β-羟基丁酰化修饰（Kbhb）可能介导多个重要细胞进程，并鉴定了Kbhb的调控酶及底物谱。然而，作为类似的酮体代谢产物乙酰乙酸，其非代谢功能及相关的分子机制尚未明确。近日，黄河课题组、赵英明团队联合韩国成均馆大学Sangkyu Lee团队，在 Advanced Science 期刊发表了题为：Identification of Histone Lysine Acetoacetylation as aDynamic Post-Translational Modification Regulated byHBO1 的研究论文。该研究鉴定了一种由乙酰乙酸驱动形成的全新组蛋白修饰——赖氨酸乙酰乙酰化（Kacac），并揭示了该新型修饰的关键调控因子HBO1。研究团队假设并验证了短链脂肪酸乙酰乙酸可作为赖氨酸乙酰乙酰化修饰（Kacac）的前体。运用生物大分子高分辨质谱、稳定同位素标记及免疫学等手段，研究团队鉴定并验证了组蛋白Kacac修饰在人、小鼠、斑马鱼的细胞中广泛存在。进一步的细胞和体外水平实验证实了HBO1可以催化Kacac，表明HBO1是Kacac的“Writer”。研究td 通过对HDAC1-11进行筛选，发现了HDAC3具有去除Kacac的催化活性，表明HDAC3是赖氨酸Kacac的“Eraser”。进而，研究发现通过乙酰乙酸乙酯（EAA）和酮体生成抑制剂处理细胞可以动态调节Kacac修饰水平。通过深入的Kacac组学分析，该研究在哺乳动物组蛋白上鉴定到33个独特的Kacac位点，描绘了组蛋白Kacac在物种和器官之间的底物谱。对Kacac修饰底物的进一步分析揭示了酮体的非代谢功能。

2023-07-06

·生物谷

Adv Sci | 上海药物所合作发现全新蛋白质修饰类型——赖氨酸乙酰乙酰化

细胞代谢为生命过程提供能量，同时代谢物可共价修饰蛋白质来发挥信号传导功能。虽然许多代谢物在代谢通路中的作用广为人知，但它们介导细胞信号调控的功能仍有待探索。酮体（包括丙酮，乙酰乙酸和β-羟基丁酸）为脂质代谢产物，在葡萄糖缺乏的状态下，肝脏产生的酮体可以用作多种组织的替代能源，与多种病理生理状态密切相关。芝加哥大学赵英明教授团队和中国科学院上海药物研究所黄河课题组前期合作研究揭示β-羟基丁酸驱动的赖氨酸β-羟基丁酰化修饰（Kbhb）可能介导多个重要细胞进程，并鉴定了Kbhb的调控酶及底物谱。然而，作为类似的酮体代谢产物乙酰乙酸，其非代谢功能及相关的分子机制尚未明确。基于上述科学问题，黄河课题组与赵英明教授团队、韩国成均馆大学Sangkyu Lee教授团队合作，鉴定了一种由乙酰乙酸驱动形成的全新组蛋白修饰—赖氨酸乙酰乙酰化（Kacac），并揭示了该新型修饰的关键调控因子HBO1。该研究成果以“Identification of Histone Lysine Acetoacetylation as aDynamic Post-Translational Modification Regulated byHBO1”为题于北京时间6月29日在线发表于Advanced Science杂志。研究团队假设并验证了短链脂肪酸乙酰乙酸可以作为赖氨酸乙酰乙酰化修饰(Kacac)的前体。运用生物大分子高分辨质谱、稳定同位素标记以及免疫学等多种手段，科研人员鉴定并验证了组蛋白Kacac修饰在人、小鼠、斑马鱼的细胞中广泛存在。进一步的细胞和体外水平实验证实了HBO1可以催化Kacac，表明了HBO1是Kacac的“Writer”。另一方面，研究人员通过对HDAC1-11进行筛选，发现HDAC3具有去除Kacac的催化活性, 表明HDAC3是赖氨酸Kacac的“Eraser”。图1、赖氨酸乙酰乙酰化的鉴定随后，研究团队发现通过乙酰乙酸乙酯（EAA）和酮体生成抑制剂处理细胞可以动态调节Kacac修饰水平。通过深入的Kacac组学分析，该研究在哺乳动物组蛋白上成功鉴定到了33个独特的Kacac位点，描绘了组蛋白Kacac在物种和器官之间的底物谱。对Kacac修饰底物的进一步分析揭示了酮体的非代谢功能。图2、HBO1催化乙酰乙酰转移酶活性该研究首次揭示了一种全新的蛋白修饰类型Kacac，探索了调控Kacac的关键酶，拓展了Kacac调控的蛋白质底物谱，阐释了Kacac参与细胞代谢调控进程的新机制、新途径，为进一步揭示Kacac修饰在各种生理、病理条件下的作用提供了理论依据。全文链接https://onlinelibrary.wiley.com/doi/epdf/10.1002/advs.202300032会议推荐会议详情会议名称：2023（第14届）细胞与基因治疗国际研讨会暨抗体工程与创新免疫治疗技术论坛暨2023细胞免疫治疗专业委员会年会主办单位：生物谷、梅斯医学、同济大学附属同济医院、南京可缘大会时间：9月22-23日大会地点：上海大会规模：1500人2010年至今，生物谷联合各合作单位已经顺利召开了13届细胞与基因治疗国际研讨会，与全球致力于细胞治疗行业同仁们一同成长沉淀，在提供行业信息交流平台的同时，也为基础研究提供了技术/产品等产业化的孵化平台。基于此，本届会议将继续以转化医学为切入点，以基础研究与临床应用相结合，针对细胞治疗的临床前沿研究、临床监管、治疗规范、细胞治疗安全性，免疫细胞新型疗法、实体瘤治疗、干细胞与癌症、抗体药物、核酸药物、基因编辑、肿瘤免疫治疗等热门议题进行讨论，诚邀国内外产学研医专家共聚，共绘产业发展新蓝图！长按识别二维码立即报名参会

免疫疗法抗体药物偶联物基因疗法

2023-07-06

·生物谷

研究发现全新蛋白质修饰类型

细胞代谢为生命过程提供能量。同时，代谢物可共价修饰蛋白质来发挥信号传导功能。虽然许多代谢物在代谢通路中的作用广为人知，但它们介导细胞信号调控的功能有待探索。酮体（包括丙酮、乙酰乙酸和β-羟基细胞代谢为生命过程提供能量。同时，代谢物可共价修饰蛋白质来发挥信号传导功能。虽然许多代谢物在代谢通路中的作用广为人知，但它们介导细胞信号调控的功能有待探索。酮体（包括丙酮、乙酰乙酸和β-羟基丁酸）为脂质代谢产物。在葡萄糖缺乏的状态下，肝脏产生的酮体可用作多种组织的替代能源，且与多种病理生理状态密切相关。美国芝加哥大学教授赵英明团队和中国科学院上海药物研究所研究员黄河课题组前期合作揭示了β-羟基丁酸驱动的赖氨酸β-羟基丁酰化修饰（Kbhb）可能介导多个重要细胞进程，并鉴定了Kbhb的调控酶及底物谱。然而，作为类似的酮体代谢产物乙酰乙酸，其非代谢功能及相关的分子机制尚未明确。基于上述科学问题，黄河课题组、赵英明团队，联合韩国成均馆大学教授Sangkyu Lee团队，鉴定了一种由乙酰乙酸驱动形成的全新组蛋白修饰——赖氨酸乙酰乙酰化（Kacac），并揭示了该新型修饰的关键调控因子HBO1。相关研究成果以Identification of Histone Lysine Acetoacetylation as aDynamic Post-Translational Modification Regulated byHBO1为题，在线发表在《科学进展》（Advanced Science）上。该团队假设并验证了短链脂肪酸乙酰乙酸可作为赖氨酸乙酰乙酰化修饰（Kacac）的前体。运用生物大分子高分辨质谱、稳定同位素标记及免疫学等手段，科研人员鉴定并验证了组蛋白Kacac修饰在人、小鼠、斑马鱼的细胞中广泛存在。进一步的细胞和体外水平实验证实了HBO1可以催化Kacac，表明HBO1是Kacac的“Writer”。研究人员通过对HDAC1-11进行筛选，发现了HDAC3具有去除Kacac的催化活性，表明HDAC3是赖氨酸Kacac的“Eraser”。进而，研究发现通过乙酰乙酸乙酯（EAA）和酮体生成抑制剂处理细胞可以动态调节Kacac修饰水平。通过深入的Kacac组学分析，该研究在哺乳动物组蛋白上鉴定到33个独特的Kacac位点，描绘了组蛋白Kacac在物种和器官之间的底物谱。对Kacac修饰底物的进一步分析揭示了酮体的非代谢功能。该研究首次揭示了全新的蛋白修饰类型Kacac，探索了调控Kacac的关键酶，拓展了Kacac调控的蛋白质底物谱，阐释了Kacac参与细胞代谢调控进程的新机制和新途径，为进一步剖析Kacac修饰在各种生理、病理条件下的作用提供了理论依据。研究工作得到韩国国家研究基金会、美国国立卫生研究院、国家自然科学基金委员会和上海市的支持。韩国庆北大学的科研人员参与研究。图1. 赖氨酸乙酰乙酰化的鉴定