更新于：2024-11-01

ZSCAN4

更新于：2024-11-01

基本信息

别名

FLJ35105、zinc finger and SCAN domain containing 4、Zinc finger and SCAN domain-containing protein 4

+ [3]

简介

Embryonic stem (ES) cell-specific transcription factor required to regulate ES cell pluripotency. Binds telomeres and plays a key role in genomic stability in ES cells by regulating telomere elongation. Acts as an activator of spontaneous telomere sister chromatid exchange (T-SCE) and telomere elongation in undifferentiated ES cells (By similarity).

关联

项与 ZSCAN4 相关的药物

EXG-34217

靶点

ZSCAN4

作用机制

ZSCAN4基因刺激剂 [+1]

在研机构

Elixirgen Therapeutics, Inc.初创企业

原研机构

Elixirgen Therapeutics, Inc.初创企业

在研适应症

骨髓衰竭疾病 [+1]

非在研适应症

先天性角化不良 [+2]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

EXG-001

靶点

ZSCAN4

作用机制

ZSCAN4基因刺激剂

在研机构

Elixirgen Therapeutics, Inc.初创企业 [+1]

原研机构

Elixirgen Therapeutics, Inc.初创企业 [+1]

在研适应症

先天性角化不良

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

CN118178646

专利挖掘

靶点

ZSCAN4

作用机制-

在研机构

Zhengzhou Chuangsheng Biological Engineering Co., Ltd.

原研机构

Zhengzhou Chuangsheng Biological Engineering Co., Ltd.

在研适应症

胃肠道肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

项与 ZSCAN4 相关的临床试验

NCT05868499 / Enrolling by invitation临床1期

Long Term Follow-up Study in Patients With Telomere Biology Disorders With Bone Marrow Failure Who Completed Study EXG-US-01

This is a long-term rollover follow-up study for Phase I/II study (Protocol EXG-US-01).

开始日期2024-01-01

申办/合作机构

Elixirgen Therapeutics, Inc.初创企业

NCT04211714 / Recruiting临床1期

A Phase I/II Study to Evaluate the Safety and Tolerability of EXG34217 in Patients With Telomere Biology Disorders With Bone Marrow Failure

This is a Phase I/II, open label, single center study to assess the safety and tolerability of EXG34217 in bone marrow failure patients with telomere biology disorders.

开始日期2021-04-08

申办/合作机构

Elixirgen Therapeutics, Inc.初创企业

100 项与 ZSCAN4 相关的临床结果

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100 项与 ZSCAN4 相关的转化医学

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0 项与 ZSCAN4 相关的专利（医药）

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114

项与 ZSCAN4 相关的文献（医药）

2024-08-26·Journal of Molecular Cell Biology

Telomeric DNA breaks in human induced pluripotent stem cells trigger ATR-mediated arrest and telomerase-independent telomere damage repair

Article

作者: Johnson, F Brad ; Beveridge, Brinley M ; Estep, Katrina N ; Tobias, John W ; Fernandez, Rafael J

AbstractAlthough mechanisms of telomere protection are well-defined in differentiated cells, how stem cells sense and respond to telomere dysfunction, in particular telomeric double-strand breaks (DSBs), is poorly characterized. Here, we report the DNA damage signaling, cell cycle, and transcriptome changes in human induced pluripotent stem cells (iPSCs) in response to telomere-internal DSBs. We engineer human iPSCs with an inducible TRF1-FokI fusion protein to acutely induce DSBs at telomeres. Using this model, we demonstrate that TRF1-FokI DSBs activate an ATR-dependent DNA damage response, which leads to p53-independent cell cycle arrest in G2. Using CRISPR–Cas9 to cripple the catalytic domain of telomerase reverse transcriptase, we show that telomerase is largely dispensable for survival and lengthening of TRF1-FokI-cleaved telomeres, which instead are effectively repaired by robust homologous recombination (HR). In contrast to HR-based telomere maintenance in mouse embryonic stem cells, where HR causes ZSCAN4-dependent extension of telomeres beyond their initial lengths, HR-based repair of telomeric breaks is sufficient to maintain iPSC telomeres at a normal length, which is compatible with sustained survival of the cells over several days of TRF1-FokI induction. Our findings suggest a previously unappreciated role for HR in telomere maintenance in telomerase-positive iPSCs and reveal distinct iPSC-specific responses to targeted telomeric DNA damage.

2024-02-01·DNA Research

ZSCAN4-binding motif—TGCACAC is conserved and enriched in CA/TG microsatellites in both mouse and human genomes

Article

作者: Ishiguro, Kei-Ichiro ; Akiyama, Tomohiko ; Ko, Shigeru B H ; Chikazawa, Nana ; Yukawa, Masashi ; Ko, Minoru S H

AbstractThe Zinc finger and SCAN domain containing 4 (ZSCAN4) protein, expressed transiently in pluripotent stem cells, gametes, and early embryos, extends telomeres, enhances genome stability, and improves karyotypes in mouse embryonic stem (mES) cells. To gain insights into the mechanism of ZSCAN4 function, we identified genome-wide binding sites of endogenous ZSCAN4 protein using ChIP-seq technology in mouse and human ES cells, where the expression of endogenous ZSCAN4 was induced by treating cells with retinoic acids or by overexpressing DUX4. We revealed that both mouse and human ZSCAN4 bind to the TGCACAC motif located in CA/TG microsatellite repeats, which are known to form unstable left-handed duplexes called Z-DNA that can induce double-strand DNA breaks and mutations. These ZSCAN4 binding sites are mostly located in intergenic and intronic regions of the genomes. By generating ZSCAN4 knockout in human ES cells, we showed that ZSCAN4 does not seem to be involved in transcriptional regulation. We also found that ectopic expression of mouse ZSCAN4 enhances the suppression of chromatin at ZSCAN4-binding sites. These results together suggest that some of the ZSCAN4 functions are mediated by binding to the error-prone regions in mouse and human genomes.

2024-01-01·Cell Proliferation

Overcoming the H4K20me3 epigenetic barrier improves somatic cell nuclear transfer reprogramming efficiency in mice

Article

作者: Presicce, Giorgio Antonio ; Liu, Zhihui ; Xia, Yuhan ; An, Liyou ; Wang, Weiguo ; Gao, Yuan ; Du, Fuliang ; Wang, Zhisong ; Li, Mingyang

AbstractEpigenetic reprogramming during fertilization and somatic cell nuclear transfer (NT) is required for cell plasticity and competent development. Here, we characterize the epigenetic modification pattern of H4K20me3, a repressive histone signature in heterochromatin, during fertilization and NT reprogramming. Importantly, the dynamic H4K20me3 signature identified during preimplantation development in fertilized embryos differed from NT and parthenogenetic activation (PA) embryos. In fertilized embryos, only maternal pronuclei carried the canonical H4K20me3 peripheral nucleolar ring‐like signature. H4K20me3 disappeared at the 2‐cell stage and reappeared in fertilized embryos at the 8‐cell stage and in NT and PA embryos at the 4‐cell stage. H4K20me3 intensity in 4‐cell, 8‐cell, and morula stages of fertilized embryos was significantly lower than in NT and PA embryos, suggesting aberrant regulation of H4K20me3 in PA and NT embryos. Indeed, RNA expression of the H4K20 methyltransferase Suv4‐20h2 in 4‐cell fertilized embryos was significantly lower than NT embryos. Knockdown of Suv4‐20h2 in NT embryos rescued the H4K20me3 pattern similar to fertilized embryos. Compared to control NT embryos, knockdown of Suv4‐20h2 in NT embryos improved blastocyst development ratios (11.1% vs. 30.5%) and full‐term cloning efficiencies (0.8% vs. 5.9%). Upregulation of reprogramming factors, including Kdm4b, Kdm4d, Kdm6a, and Kdm6b, as well as ZGA‐related factors, including Dux, Zscan4, and Hmgpi, was observed with Suv4‐20h2 knockdown in NT embryos. Collectively, these are the first findings to demonstrate that H4K20me3 is an epigenetic barrier of NT reprogramming and begin to unravel the epigenetic mechanisms of H4K20 trimethylation in cell plasticity during natural reproduction and NT reprogramming in mice.

项与 ZSCAN4 相关的新闻（医药）

2024-09-25

·GlobeNewswire-Health Care

Elixirgen Therapeutics Receives Rare Pediatric Disease Designation for EXG-34217 in Dyskeratosis Congenita and Related Telomere Biology Disorders

Elixirgen Therapeutics is currently enrolling patients in its Phase 1/2 trial evaluating EXG-34217 in patients with telomere biology disorders at Cincinnati Children’s Hospital Medical CenterBALTIMORE, Sept. 25, 2024 (GLOBE NEWSWIRE) -- Elixirgen Therapeutics, Inc., a clinical-stage biotechnology company focused on the discovery, development and commercialization of therapies using its mRNA platforms, today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation (RPDD) to EXG-34217 for the treatment of patients with dyskeratosis congenita and related telomere biology disorders (DC/TBD). EXG-34217 is comprised of autologous CD34+ hematopoietic stem cells (HSCs) that have been treated ex vivo with EXG-001, a non-integrating, non-transmissible, temperature-sensitive Sendai virus vector encoding human ZSCAN4. The company is currently enrolling patients at Cincinnati Children’s Hospital Medical Center for a Phase 1/2 trial (NCT04211714). “We’re pleased with the FDA’s decision to grant EXG-34217 RPDD for the treatment of DC/TBD, a rare group of diseases that result in abnormally short telomeres that can lead to bone marrow failure and other serious health conditions,” said Aki Ko, chief executive officer of Elixirgen Therapeutics. “The RPDD is a recognition of the significant unmet need in this space and the potential of EXG-34217, and we look forward to working with the FDA as we continue to advance this program.” The FDA grants RPDD for serious or life-threatening diseases that affect fewer than 200,000 people in the United States and primarily affect patients less than 18 years of age. If a marketing application for EXG-34217 for the treatment of DC/TBDs is approved by the FDA, Elixirgen Therapeutics may be eligible to receive a Priority Review Voucher (PRV) that could be used to receive accelerated review of any subsequent application. About Elixirgen Therapeutics, Inc. Elixirgen Therapeutics, Inc. is a clinical-stage biotechnology company focused on the discovery, development and commercialization of therapies using its mRNA platforms and ZSCAN4 technology. The company has one ongoing (NCT04211714) and one completed (NCT04863131) Phase 1/2 clinical trial. For more information, visit ElixirgenTx.com. Forward-Looking Statements This press release may contain "forward-looking" statements. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in pharmaceutical research and development. Any forward-looking statements in this press release speak only as of the date of this press release, and Elixirgen Therapeutics undertakes no obligation to update or revise the statements in the future, even if new information becomes available. Contact Media Relations:Madelin Hawtin LifeSci Communicationsmhawtin@lifescicomms.com

临床研究优先审批临床申请

2024-06-11

·生物探索

Nat Genet | 清华大学刘念团队发现转座子LINE-1转录选择性激活远程基因表达

引言二十世纪五十年代，Barbara McClintock在玉米中发现一类能在基因组中移动、改变自身位置的DNA序列。当时，人们普遍认为基因在染色体上只能是固定不变的。这一惊世骇俗的发现打破了人们的认知，然而却并未获得认可。直到三十多年后，她和这些可以在基因组中移动的DNA序列终于等到了1983年诺贝尔生理学或医学奖——迟来的肯定。这些序列就是——转座子。人类基因组中有接近一半的序列由转座子构成，其中，LINE-1（Long interspersed nuclear element-1）占据了人类~17%的基因组序列，它也是目前人体内唯一活跃且具有自主逆转录转座能力的逆转录转座子。尽管在体细胞中LINE-1表达通常受到抑制，但在人和小鼠早期胚胎发育的合子基因组激活（zygotic genome activation，ZGA）过程中LINE-1却高表达。这不仅说明LINE-1的表达受到极其严格和精确的调控，而且暗示LINE-1的表达在关键生理过程具有重要作用。然而，关于LINE-1表达是如何被调控的，LINE-1在基因调控中的功能以及ZGA中的作用还知之甚少。 2024年6月7日17时，清华大学生命学院刘念团队在 Nature Genetics 期刊发表了题为：LINE-1 transcription activates long-range gene expression 的研究论文。该研究提供了第一个关于LINE-1表达调控的全基因组筛选结果，系统性的鉴定并验证了LINE-1作为增强子的功能和作用，揭示了LINE-1在长程基因激活中的广泛影响，并阐释了LINE-1转录如何帮助植入前胚胎中ZGA过程的成功进行，深化了我们对LINE-1表达在哺乳动物发育和疾病中的调节和功能作用的理解。刘念课题组长期从事逆转录转座子调控和功能研究。在之前的工作中，系统鉴定了LINE-1转座过程的调控因子（Liu et al. Nature 2018），并发现LINE-1可以作为拓扑结构域边界（Hong et al. Molecualr Cell 2024）。这项研究利用LINE-1 5'UTR驱动的报告基因在人类细胞中进行全基因组CRISPR-Cas9筛选，鉴定了171个LINE-1表达抑制因子和332个激活因子。这些调控因子参与功能多样的调控通路。有意思的是，很多的LINE-1表达调控因子与增强子调控和功能相关（KMT2D、CTBP1、METTL3、METTL14等），这提示LINE-1可能具有增强子活性。通过系统挖掘全基因组自转录活性调控区测序（STARR-seq）数据，研究团队发现LINE-1 5'UTR具有增强子特征，可以通过不依赖其位置或方向的方式激活基因表达。刘念团队进一步揭示了LINE-1在哺乳动物早期胚胎发育中的生物学功能。他们发现，LINE-1在小鼠早期2细胞阶段就开始表达，并且与minor ZGA基因（如Obox4、Zscan4等）接触并激活。抑制LINE-1转录或敲除LINE-1 RNA都能显著降低ZGA基因的表达，并阻碍小鼠胚胎发育在2-4细胞阶段。有趣的是，与恒河猴相比，人类基因组中特异存在的、进化上较年轻的LINE-1 PA1-5元件显著增强了人早期胚胎中ZGA基因的表达，说明LINE-1在基因组上的持续插入已经改变了灵长类动物ZGA基因表达的调控网络。由于LINE-1的活跃转座使其仍在人基因组中扩增，因此LINE-1可能在人类基因组中持续增添新的顺式DNA调控元件，进而影响着人类的多种疾病和发育过程。 L1的转录水平被功能多样的基因所精密调控，也决定着L1选择性地接触并激活远程基因表达的功能，影响着早期胚胎发育中的ZGA，也可能影响衰老、癌症和神经系统性疾病等（左）。L1转录激活了小鼠早期胚胎发育中的第一波转录行为（minor ZGA）（右）。（Credit: Nature Genetics）总而言之，该研究提供了功能多样的LINE-1表达调控因子，发现并验证了LINE-1 5' UTR作为增强子在早期胚胎发育阶段通过转录依赖的方式直接与ZGA基因相互作用激活基因表达。该工作为研究LINE-1的调控网络提供了丰富的资源，揭示了LINE-1表达调控的复杂性和多样性；解释了为什么LINE-1在胚胎发育过程中被激活，为理解LINE-1在基因组中的功能提供了新的视角。原文链接 https://www.nature.com/articles/s41588-024-01789-5 责编|探索君排版|探索君文章来源|“生物世界” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

基因疗法临床研究

2024-06-07

·生物探索

Cell | 全能细胞的培育：北京大学杜鹏团队合作通过剪接抑制技术实现人类全能类合子细胞的稳定传代

引言合子的分裂产生全能的卵裂球。在人类8细胞卵裂球中，合子基因组激活(zygotic genome activation, ZGA)启动了个体发生程序。然而，在人类细胞中获取和维持全能性面临着重大挑战。 2024年6月5日，北京大学杜鹏团队在Cell 在线发表题为“Capturing totipotency in human cells through spliceosomal repression”的研究论文，该研究表明通过剪接体能够抑制在人细胞中捕获全能性。该研究实现了人类全能卵裂球样细胞(hTBLCs)的培养。研究发现剪接抑制可以短暂地将人类多能干细胞重编程为ZGAlike细胞( ZLCs)，并在长期传代后转变为稳定的hTBLCs。与报道的8细胞样细胞(8CLCs)不同， ZLCs和hTBLCs广泛沉默多能基因。有趣的是， ZLCs激活了一组特定的ZGA特异性基因，而hTBLCs富含pre-ZGA特异性基因。在自发分化过程中，hTBLCs重新进入中间的ZLC阶段，并进一步产生外胚层(EPI)-、原始内胚层(PrE)-和滋养外胚层(TE)样谱系，有效地再现了人类着床前的发育。hTBLCs具有胚胎和胚胎外发育潜能，可以在体外不需要外部细胞信号的情况下自主产生囊胚样结构。总之，该研究提供了人类细胞全能性的关键标准和见解。受精后，受精卵基因组在一开始是沉默的。最初的几轮细胞分裂依赖于母体物质，直到合子基因组激活(ZGA)发生，这在不同物种中是保守的。在人类中，ZGA发生在8细胞卵裂球中，而在小鼠中，它发生在2细胞卵裂球中。受精卵和早期卵裂球代表全能性，它严格地由产生整个生物体的能力和产生胚胎和胚胎外组织的双向能力来定义。全能卵裂球启动细胞命运的第一轮决定，产生滋养外胚层(TE)，形成胚外胎盘组织，以及内细胞团(ICM)，后者进一步分化为原始内胚层(PrE)和多能外胚层(EPI)谱系，分别产生胚外卵黄囊和整个胚胎组织。从ICM细胞中获得并建立了人类胚胎干细胞(hESC)系将成纤维细胞重编程为诱导多能干细胞(iPSCs)已经克服了与ESC来源和伦理问题相关的限制。目前，多能hESCs和iPSCs广泛应用于基础研究和转化医学。hESCs和iPSCs的分化能力是决定干细胞衍生功能细胞类型和质量的基础，这方面的研究仍然有限。最近，一种表达ZGA特异性基因的8细胞样细胞(8CLCs)，特别是在8细胞卵裂球中富集，包括ZSCAN4和DUXA，在初始多能ESC培养条件下以极低的百分比被捕获。值得注意的是，这些8CLCs是亚稳态的，可以迅速恢复到多能状态，因此不能稳定地培养多次传代。到目前为止，接近卵裂球早期阶段的人类细胞还不能在体外稳定地培养。模式图（Credit: Cell）该研究利用hTBLCs的PrE -ZGA特征，建立了hTBLCs自发分化和囊胚形成系统，在该系统中，hTBLCs通过ZLC样阶段过渡并经历两次细胞命运决定，导致EPI、TE和PrE谱系平行产生。这使得人类首次实现了对整个胚胎着床前发育的重塑。值得注意的是，这两个系统都不需要外部信号操作。这与之前基于hESC/iPSC的多能诱导系统不同，后者需要多种细胞信号因子，如A83-01、PD0325901和BMP4，以及长时间传代和集落选择来产生胚外TE或PrE细胞，反映了典型的反分化过程。结果表明，多能hESC/iPSC或hEPSCs在相同的条件下不能产生TE/PrE谱系或囊胚样结构。因此，hTBLCs具有hESCs/iPSCs或hEPSCs所没有的独特的全能性，并建议采用类似的细胞自发分化策略，不需要人工细胞信号传导操作和长期传代，作为评估体外培养的全能性样干细胞的关键标准。原文链接 https://www.cell.com/cell/abstract/S0092-8674(24)00519-1 责编|探索君排版|探索君文章来源|“iNature” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床研究