更新于：2024-05-01

HDAC4

组蛋白去乙酰化酶-4

更新于：2024-05-01

基本信息

别名

BDMR、brachydactyly-mental retardation syndrome、HA6116

+ [7]

简介

Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256).

关联

项与 HDAC4 相关的药物

KAR-1641

靶点

HDAC4 x TNF-α

作用机制

HDAC4抑制剂 [+1]

在研机构-

原研机构

Karus Therapeutics Ltd.

在研适应症-

非在研适应症

炎症

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 HDAC4 相关的临床结果

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100 项与 HDAC4 相关的转化医学

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0 项与 HDAC4 相关的专利（医药）

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1,452

项与 HDAC4 相关的文献（医药）

2024-03-01·Protein science : a publication of the Protein Society

The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation.

Article

作者: Markus Schweipert ; Thomas Nehls ; Anton Frühauf ; Cecilé Debarnot ; Adarsh Kumar ; Stefan Knapp ; Frederik Lermyte ; Franz-Josef Meyer-Almes

Human histone deacetylase 4 (HDAC4) is a key epigenetic regulator involved in a number of important cellular processes. This makes HDAC4 a promising target for the treatment of several cancers and neurodegenerative diseases, in particular Huntington's disease. HDAC4 is highly regulated by phosphorylation and oxidation, which determine its nuclear or cytosolic localization, and exerts its function through multiple interactions with other proteins, forming multiprotein complexes of varying composition. The catalytic domain of HDAC4 is known to interact with the SMRT/NCOR corepressor complex when the structural zinc-binding domain (sZBD) is intact and forms a closed conformation. Crystal structures of the HDAC4 catalytic domain have been reported showing an open conformation of HDAC4 when bound to certain ligands. Here, we investigated the relevance of this HDAC4 conformation under physiological conditions in solution. We show that proper zinc chelation in the sZBD is essential for enzyme function. Loss of the structural zinc ion not only leads to a massive decrease in enzyme activity, but it also has serious consequences for the overall structural integrity and stability of the protein. However, the Zn²⁺ free HDAC4 structure in solution is incompatible with the open conformation. In solution, the open conformation of HDAC4 was also not observed in the presence of a variety of structurally divergent ligands. This suggests that the open conformation of HDAC4 cannot be induced in solution, and therefore cannot be exploited for the development of HDAC4-specific inhibitors.

2024-02-21·Cell death & disease

Transcription of endogenous retroviruses in senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence.

Article

作者: Eros Di Giorgio ; Liliana Ranzino ; Vanessa Tolotto ; Emiliano Dalla ; Matteo Burelli ; Nicolò Gualandi ; Claudio Brancolini

An important epigenetic switch marks the onset and maintenance of senescence. This allows transcription of the genetic programs that arrest the cell cycle and alter the microenvironment. Transcription of endogenous retroviruses (ERVs) is also a consequence of this epigenetic switch. In this manuscript, we have identified a group of ERVs that are epigenetically silenced in proliferating cells but are upregulated during replicative senescence or during various forms of oncogene-induced senescence, by RAS and Akt, or after HDAC4 depletion. In a HDAC4 model of senescence, removal of the repressive histone mark H3K27me3 is the plausible mechanism that allows the transcription of intergenic ERVs during senescence. We have shown that ERVs contribute to the accumulation of dsRNAs in senescence, which can initiate the antiviral response via the IFIH1-MAVS signaling pathway and thus contribute to the maintenance of senescence. This pathway, and MAVS in particular, plays an active role in shaping the microenvironment and maintaining growth arrest, two essential features of the senescence program.

2024-02-08·Bone

Epigenetic regulators controlling osteogenic lineage commitment and bone formation.

Review

作者: Parisa Dashti ; Eric A Lewallen ; Jonathan A R Gordon ; Martin A Montecino ; James R Davie ; Gary S Stein ; Johannes P T M van Leeuwen ; Bram C J van der Eerden ; Andre J van Wijnen

Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by nucleosome-based chromatin architecture that limits the accessibility of lineage-specific gene regulatory DNA sequences and sequence-specific transcription factors. From a developmental perspective, bone-specific gene expression must be suppressed during the early stages of embryogenesis to prevent the premature mineralization of skeletal elements during fetal growth in utero. Hence, bone formation is initially inhibited by gene suppressive epigenetic regulators, while other epigenetic regulators actively support osteoblast differentiation. Prominent epigenetic regulators that stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), lysine deacetylases (e.g., HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine methyl transferases (e.g., PRMT1, PRMT4/CARM1, PRMT5), dioxygenases (e.g., TET2), bromodomain proteins (e.g., BRD2, BRD4) and chromodomain proteins (e.g., CBX1, CBX2, CBX5). This narrative review provides a broad overview of the covalent modifications of DNA and histone proteins that involve hundreds of enzymes that add, read, or delete these epigenetic modifications that are relevant for self-renewal and differentiation of mesenchymal stem cells, skeletal stem cells and osteoblasts during osteogenesis.

项与 HDAC4 相关的新闻（医药）

2023-12-22

·生物谷

Clin Epigenet：慢性偏头痛研究或能揭示降低机体偏头痛频率的特殊遗传学机制

来自昆士兰理工大学等机构的科学家们通过研究揭示了慢性偏头痛患者在逐渐停用偏头痛药物后机体偏头痛频率降低背后的生物学机制。慢性偏头痛是一种高度致残的亚型偏头痛，其影响着近2%的普通人群，理解偏头痛的慢性化对于开发更好的疗法和预防性策略至关重要，偏头痛慢性化的一种重要因素就是急性头痛药物的过度使用，然而，发作性偏头痛转化为慢性偏头痛背后的分子机制，目前研究人员尚未阐明。近日，一篇发表在国际杂志Clinical Epigenetics上题为“Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study”的研究报告中，来自昆士兰理工大学等机构的科学家们通过研究揭示了慢性偏头痛患者在逐渐停用偏头痛药物后机体偏头痛频率降低背后的生物学机制。文章中，研究人员揭示了他们如何发现从发作性偏头痛到慢性偏头痛转变过程中所涉及的两个基因的表观遗传学改变。研究者表示，慢性偏头痛是大约2%的普通人群所面临的主要头痛问题；研究者Divya Mehta说道，过度使用缓解急性头痛和其它药物是慢性偏头痛发生发展和维持的一个重要因素。如果患者每月15天或更多的时间会头痛，且会持续3个月或更长时间，其中有8天符合偏头痛的标准，那么研究人员就将这种偏头痛归类为慢性偏头痛，因此这或许是一种高度致残的偏头痛类型。如今研究人员开始理解偏头痛慢性化的过程（即某些偏头痛患者的疾病发作越来越频繁），以及如何逆转这一过程。研究人员调查了DNA甲基化的纵向改变，DNA甲基化是一种表观遗传学修饰，是为了对包括治疗性药物在内的环境因素产生反应而将在DNA分子上添加化学标签，从而就能实现基因的开启或关闭。慢性偏头痛研究或能揭示降低机体偏头痛频率的特殊遗传学机制。图片来源：Clinical Epigenetics (2023). DOI:10.1186/s13148-023-01604-8 文章中，研究人员对慢性偏头痛患者在药物疗法治疗开始时和停药12周后机体的血液进行采集并分析，Sutherland博士说道，我们让患者记录其头痛日志，并将每月的头痛和偏头痛天数减少50%以上的患者（应答者）与无应答者进行比较，从而识别出与其对疗法产生反应相关的DNA甲基化改变。在所有患者中，59.8%的患者在12周的停药期结束时又复发成为发作性偏头痛患者。而且研究人员发现，HDAC4基因的表观遗传学改变与急性药物停药后头痛天数的平均减少有关，DNA甲基化水平的降低与头痛天数的减少有一定关联。其次，研究者发现，MARK3基因内的DNA甲基化与偏头痛天数的平均减少有关；MARK3基因在基线时的DNA甲基化水平较低或与每月偏头痛天数减少有关，且其被发现是一种预测患者对疗法产生反应的特殊生物标志物。这些研究发现具有重大的临床意义，因为其能揭示这些基因或许能作为偏头痛的新型治疗性靶点。综上，本文研究结果表明，与疗法反应相关的HDAC4的DNA甲基化水平的纵向降低，以及基线MARK3的DNA甲基化或能作为指示偏头痛患者对疗法产生反应的早期生物标志物，从而就为揭示染色质结构和突触可塑性相关通路在偏头痛慢性化中的重要作用提供了一定的支持，并引入了HDAC4和MARK3作为新型的治疗性靶点。（生物谷Bioon.com）原始出处： Mehta, D., de Boer, I., Sutherland, H.G. et al. Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study. Clin Epigenet 15, 190 (2023). doi：10.1186/s13148-023-01604-8

临床结果临床研究

2023-05-25

·Science Daily

Keeping time: Understanding the master clock in the brain

Researchers found that, in neurons that produced the neuropeptide NMS, the interaction between molecules SIK3 and HDAC4 has a critical role in sleep regulation through both the length of the circadian period and sleep homoeostasis. Given the similarities among different mammals, new information about how the circadian system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. Most living creatures exhibit a circadian rhythm, an internal clock that repeats around every 24 hours. Now, researchers from Japan have found new details about the molecular processes that govern sleep/wake rhythms in mice. In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays a critical role in circadian behavior. Animals are able to adapt to the 24-hour cycle of light and dark in terms of both behavior and physiology via changes in the suprachiasmatic nucleus (SCN), which is the brain's master clock that synchronizes the various rhythms in the body. However, the biological activities within the SCN that induce time-specific wakefulness have not been fully characterized; the research team aimed to address this. "Most animals show a peak in activity at a specific point in the circadian cycle," explains lead author of the study Professor Masashi Yanagisawa. "Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the distinct neurons that control this process." To do this, the research team genetically manipulated levels of SIK3 in specific neuron groups in the SCN of mice. Then, they examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity with respect to the light-dark cycle. "We found that SIK3 in the SCN can influence circadian cycle length and the timing of peak arousal activity, without changing the daily sleep amount," says Professor Yanagisawa. The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have found that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons, and contributes to the sleep/wake rhythm. The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. This work was supported by the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI), Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 grant, University of Tsukuba Basic Research Support Program Type A, and Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).

2023-04-25

·Pharmaceutical Technology

Aevitas to sell sCFH asset rights to 4D Molecular

sCFH is an engineered and improved version of complement factor H. Credit: Deposition authors: Jaakola, V-P, Jokiranta, TS, Goldman, A. Visualisation author: User: Astrojan/ commons.wikimedia.org Fortress Biotech subsidiary Aevitas Therapeutics has signed an asset purchase deal to sell the proprietary rights to its short-form human complement factor H (sCFH) asset to 4D Molecular Therapeutics for $140m in cash. sCFH is an engineered and improved version of complement factor H (CFH) that can fit into adeno-associated virus (AAV) vectors with solid expression and applications confirmed in cultured human cells in vitro, in addition to various preclinical animal models in vivo. Recommended Reports Reports Bromodomain Containing Protein 4 (Protein HUNK1 or BRD4) Drugs in Development by Therapy Areas an... GlobalData Reports Histone Deacetylase 4 (Histone Deacetylase A or HDAC4 or EC 3.5.1.98) Development by Therapy Area... GlobalData View all Reinstating CFH function by employing the sCFH protein could restore normal complement regulation and minimise retinal injury that manifests as progressive geographic atrophy (GA). Aevitas will receive the payment as potential late-stage development, regulatory and sales milestones. The firm will also receive single-digit royalties on net sales. 4DMT will be responsible for licence payments to the University of Pennsylvania, where the Perelman School of Medicine’s pharmacology professor, Dr Wenchao Song, jointly invented and developed the sCFH technology. Fortress chairman, president and CEO and Aevitas executive chairman Lindsay A Rosenwald stated: “This agreement with 4DMT allows Fortress to focus on acquiring and developing clinical-stage treatments, while potentially expediting the development and commercialisation of this preclinical sCFH technology. “Partnering with 4DMT further validates the Fortress business model of identifying and developing promising treatments for patients, while pursuing opportunities that potentially maximise shareholder value. “We look forward to 4DMT using their vector platform to continue the development of the sCFH asset to potentially treat geographic atrophy (GA) and other diseases.”