更新于：2024-11-01

HMGB2

更新于：2024-11-01

基本信息

别名

high mobility group box 2、High mobility group protein 2、High mobility group protein B2

+ [3]

简介

Multifunctional protein with various roles in different cellular compartments. May act in a redox sensitive manner. In the nucleus is an abundant chromatin-associated non-histone protein involved in transcription, chromatin remodeling and V(D)J recombination and probably other processes. Binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity (PubMed:7797075, PubMed:11909973, PubMed:19522541, PubMed:18413230, PubMed:19965638, PubMed:20123072). Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS) (By similarity). Proposed to be involved in the innate immune response to nucleic acids by acting as a promiscuous immunogenic DNA/RNA sensor which cooperates with subsequent discriminative sensing by specific pattern recognition receptors (By similarity). In the extracellular compartment acts as a chemokine. Promotes proliferation and migration of endothelial cells implicating AGER/RAGE (PubMed:19811285). Has antimicrobial activity in gastrointestinal epithelial tissues (PubMed:23877675). Involved in inflammatory response to antigenic stimulus coupled with pro-inflammatory activity (By similarity). Involved in modulation of neurogenesis probably by regulation of neural stem proliferation (By similarity). Involved in articular cartilage surface maintenance implicating LEF1 and the Wnt/beta-catenin pathway (By similarity).

关联

项与 HMGB2 相关的药物

Inflachromene

靶点

HMGB1 x HMGB2

作用机制

HMGB1抑制剂 [+1]

在研机构

Seoul National University

原研机构

Seoul National University

在研适应症

癫痫 [+1]

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

100 项与 HMGB2 相关的临床结果

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100 项与 HMGB2 相关的转化医学

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0 项与 HMGB2 相关的专利（医药）

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682

项与 HMGB2 相关的文献（医药）

2024-12-31·Renal Failure

The transcription factor HMGB2 indirectly regulates APRIL expression and Gd-IgA1 production in patients with IgA nephropathy

Article

作者: Sun, Shuaigang ; Zhang, Wenhui ; Zhao, Zhanzheng ; Tian, Huijuan ; Zhai, Yaling

BACKGROUNDIgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Proliferation-inducing ligand (APRIL) was identified as an important cause of glycosylation deficiency of IgA1 (Gd-IgA1), which can 'trigger' IgAN. Our previous study indicated that high migration group protein B2 (HMGB2) in peripheral blood mononuclear cells from patients with IgAN was associated with disease severity, but the underlying mechanism remains unclear.MATERIALS AND METHODSThe location of HMGB2 was identified by immunofluorescence. qRT-PCR and Western blotting were used to measure HMGB2, HMGA1, and APRIL expression. Gd-IgA1 levels were detected by enzyme-linked immunosorbent assay (ELISA). In addition, we used DNA pull-down, protein profiling, and transcription factor prediction software to identify proteins bound to the promoter region of the APRIL gene. RNA interference and coimmunoprecipitation (Co-IP) were used to verify the relationships among HMGB2, high mobility group AT-hook protein 1 (HMGA1), and APRIL.RESULTSHMGB2 expression was greater in IgAN patients than in HCs and was positively associated with APRIL expression in B cells. DNA pull-down and protein profiling revealed that HMGB2 and HMGA1 bound to the promoter region of the APRIL gene. The expression levels of HMGA1, APRIL, and Gd-IgA1 were downregulated after HMGB2 knockdown. Co-IP indicated that HMGB2 binds to HMGA1. The Gd-IgA1 concentration in the supernatant was reduced after HMGA1 knockdown. HMGA1 binding sites were predicted in the promoter region of the APRIL gene.CONCLUSIONHMGB2 expression is greater in IgAN patients than in healthy controls; it promotes APRIL expression by interacting with HMGA1, thereby inducing Gd-IgA1 overexpression and leading to IgAN.

2024-12-01·International Immunopharmacology

The negative feedback loop of NF-κB/miR-202-5p/HMGB2 attenuates sepsis induced acute kidney injury

Article

作者: Chen, Jian ; Wang, Juan ; Li, Zheng ; Liu, Zhiwen

Sepsis represents a primary cause of acute kidney injury (AKI), yet the underlying mechanisms of septic AKI remain poorly understood. Thus, there exists an urgent need for a deeper understanding of its underlying mechanisms and the development of effective therapeutic strategies. Our study reveals a notable induction in microRNA-202-5p (miR-202-5p) levels within renal tubular cells in septic AKI both in vivo and in vitro models. Treatment of renal tubular cells with LPS induced NF-κB activation, which was linked to the induction of miR-202-5p. ChIP assays confirmed NF-κB binding to the miR-202-5p gene promoter upon LPS stimulation. Functionally, miR-202-5p mimics attenuated tubular cell death, kidney injury, and intra-renal inflammatory cytokine production, whereas inhibition of miR-202-5p conferred injurious effects in septic AKI. Notably, miR-202-5p suppressed the expression of High Mobility Group Box 2 (HMGB2) in both in vitro and in vivo septic AKI models. Luciferase microRNA target assays further validated HMGB2 as a direct target of miR-202-5p. Knockdown of HMGB2 inhibits LPS-induced NF-κB activation in septic AKI, as evidenced by HMGB2 siRNA transfection significantly inhibited the nuclear translocation of NF-κB. Together, these findings elucidate the NF-κB/miR-202-5p/HMGB2 negative feedback loop which can attenuate kidney injury by inhibiting renal inflammation in septic AKI. Our findings open new avenues for developing targeted therapies to manage septic AKI effectively.

2024-12-01·Cellular and Molecular Life Sciences

An i-motif-regulated enhancer, eRNA and adjacent lncRNA affect Lhb expression through distinct mechanisms in a sex-specific context

Article

作者: Sudman, Maya ; Melamed, Philippa ; Pnueli, Lilach ; Henn, Arnon ; Golan, Gil ; Kaplan, Ariel ; Naik, Sujay ; Preger-Ben Noon, Ella ; Refael, Tal

Genome-wide studies have demonstrated regulatory roles for diverse non-coding elements, but their precise and interrelated functions have often remained enigmatic. Addressing the need for mechanistic insight, we studied their roles in expression of Lhb which encodes the pituitary gonadotropic hormone that controls reproduction. We identified a bi-directional enhancer in gonadotrope-specific open chromatin, whose functional eRNA (eRNA2) supports permissive chromatin at the Lhb locus. The central untranscribed region of the enhancer contains an iMotif (iM), and is bound by Hmgb2 which stabilizes the iM and directs transcription specifically towards the functional eRNA2. A distinct downstream lncRNA, associated with an inducible G-quadruplex (G4) and iM, also facilitates Lhb expression, following its splicing in situ. GnRH activates Lhb transcription and increased levels of all three RNAs, eRNA2 showing the highest response, while estradiol, which inhibits Lhb, repressed levels of eRNA2 and the lncRNA. The levels of these regulatory RNAs and Lhb mRNA correlate highly in female mice, though strikingly not in males, suggesting a female-specific function. Our findings, which shed new light on the workings of non-coding elements and non-canonical DNA structures, reveal novel mechanisms regulating transcription which have implications not only in the central control of reproduction but also for other inducible genes.

项与 HMGB2 相关的新闻（医药）

2024-07-29

·奇点网

肝癌促癌罪犯！

*仅供医学专业人士阅读参考表观遗传促癌的机制研究，奇点糕们一直以来都没少唠，毕竟这个领域实在是博大精深又相当玄妙，不过在奇点糕的印象里，还没怎么提及过癌症中有关mRNA表观遗传修饰的研究，那就借着一项来自我国学者的最新研究，把空白给补上好啦~华中科技大学同济医学院附属同济医院陈孝平、张必翔、丁则阳团队与山西白求恩医院贺杰峰等国内研究者合作，在Cancer Communications发表的最新研究成果显示，N4-乙酰胞苷（ac4C）mRNA修饰对肝细胞癌（HCC）进展和转移有重要推动作用，而针对相关调控轴NAT10-ac4C/eEF2-HMGB2进行干预，有望为HCC精准治疗提供全新策略[1]。论文首页截图ac4C修饰及其修饰酶NAT10，近年来的关注热度一直不低，我国学者此前已经在膀胱癌、宫颈癌、结直肠癌等多种实体瘤中，发现了它们作为促癌“黑手”的角色[2-4]，且也有研究显示NAT10可能参与了调控HCC的疾病进展、转移和TKI类靶向药治疗耐药[5-6]。同济医院团队主导进行的本次研究，则希望进一步阐明NAT10-ac4C修饰促肝癌的下游机制。研究者们首先分析了HCC患者肿瘤样本及周围正常组织，证实HCC肿瘤内普遍存在RNA ac4C乙酰化修饰及NAT10的高表达，且NAT10高表达与肝癌患者较差的临床病理特征，如疾病分期较晚、属于预后相对不佳的分子亚型均显著相关；接下来，研究者们敲低了HCC细胞的NAT10水平，以分析NAT10-ac4C修饰对HCC发生发展的影响幅度和具体作用机制。实验显示，敲低NAT10使HCC细胞中含有ac4C修饰的RNA和mRNA显著减少，HCC细胞的细胞活力、克隆形成能力和迁移/远处转移能力也同时显著下降，换句话说就是敲低NAT10把HCC细胞给“废掉”了，且小鼠实验的结论也与细胞实验保持一致。而acRIP-seq测序结果显示，敲低NAT10还会全面降低HCC细胞内的mRNA翻译效率。敲低NAT10可通过降低mRNA翻译效率，直接抑制HCC细胞的增殖和转移能力接下来，研究者们综合分析多种测序方法得到的数据，发现NAT10/ac4C修饰调控的直接靶基因为HMGB2，它可能是影响mRNA翻译效率的关键；双荧光素酶实验显示，NAT10/ac4C修饰确实能提高HMGB2 mRNA的翻译效率，进而调控HCC细胞mRNA的翻译效率以促癌，过表达HMGB2即能恢复敲低NAT10对HCC细胞增殖和转移的抑制，HMGB2表达水平也与HCC患者的生存预后挂钩。不过在既往研究中，ac4C修饰往往不会通过直接结合来影响特定蛋白的表达水平，它们也需要找个“白手套”，研究者们很快就把这回的白手套揪了出来：分析显示，ac4C修饰会增强HMGB2 mRNA的2/3外显子与真核翻译延长因子2（eEF2）的结合能力，使HMGB2 mRNA的翻译增加，从而阐明了ac4C修饰上调HCC细胞HMGB2水平，进而促癌的完整调控通路。ac4C修饰可上调HMGB2 mRNA的翻译以促癌阐明调控机制之后，当然就要寻找潜在的治疗策略，为此研究者们模拟了可导致NAT10催化ac4C修饰功能下降的突变位点（G641E），并以此筛选候选治疗药物，脱颖而出的是组蛋白去乙酰化酶（HDAC）抑制剂Panobinostat，它可有效结合并阻断NAT10的“催化口袋”，进而抑制对促进HCC发生有关键意义的ac4C修饰，有望在未来参与HCC精准治疗。研究内容一图总结参考文献：[1]Liu H, Xu L, Yue S, et al. Targeting N4‐acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2‐mediated HMGB2 mRNA translation[J]. Cancer Communications, 2024. [2]Xie R, Cheng L, Huang M, et al. NAT10 drives cisplatin chemoresistance by enhancing ac4C-associated DNA repair in bladder cancer[J]. Cancer Research, 2023, 83(10): 1666-1683.[3]Jin C, Wang T, Zhang D, et al. Acetyltransferase NAT10 regulates the Wnt/β-catenin signaling pathway to promote colorectal cancer progression via ac4C acetylation of KIF23 mRNA[J]. Journal of Experimental & Clinical Cancer Research, 2022, 41: 345.[4]Chen X, Hao Y, Liu Y, et al. NAT10/ac4C/FOXP1 promotes malignant progression and facilitates immunosuppression by reprogramming glycolytic metabolism in cervical cancer[J]. Advanced Science, 2023, 10(32): 2302705.[5]Ma R, Chen J, Jiang S, et al. Up regulation of NAT10 promotes metastasis of hepatocellular carcinoma cells through epithelial-to-mesenchymal transition[J]. American Journal of Translational Research, 2016, 8(10): 4215-4223.[6]Pan Z, Bao Y, Hu M, et al. Role of NAT10-mediated ac4C-modified HSP90AA1 RNA acetylation in ER stress-mediated metastasis and lenvatinib resistance in hepatocellular carcinoma[J]. Cell Death Discovery, 2023, 9: 56.本文作者丨谭硕

信使RNA

2023-10-14

·生物谷

研究揭示人类基因组中的“年轻化”基因

随着人口老龄化的到来，衰老相关疾病的高发正成为健康挑战。延缓衰老以及增强衰老组织活力和功能维持，进而促进老年健康是亟待解决的科学难题。细胞衰老（cellular senescence）是器官衰老乃至机随着人口老龄化的到来，衰老相关疾病的高发正成为健康挑战。延缓衰老以及增强衰老组织活力和功能维持，进而促进老年健康是亟待解决的科学难题。细胞衰老（cellular senescence）是器官衰老乃至机体功能退行的本质特征和内在驱动力，为老年慢病提供了机制框架和干预思路。如何延缓甚至逆转细胞衰老，已成为生命科学领域最前沿的科学问题之一。细胞更生（cellular rejuvenation）是指通过干预手段实现衰老细胞年轻化、重现细胞活力的过程。通过重塑表观遗传和基因表达程序使细胞“返老还童”，是延缓衰老、防治衰老相关疾病的重要方法和策略之一，这使得该领域迅速成为科学家关注的焦点。中国科学院动物研究所研究员刘光慧及合作者，在国际上率先利用体细胞重编程（somatic reprogramming）技术，在衰老程度高、速度快的人类儿童早衰症（Hutchinson Gilford progeria syndrome，HGPS）成纤维细胞中导入四个Yamanaka重编程因子OSKM（Oct4、Sox2、Klf4、c-Myc），实现了衰老细胞表观基因组重塑，逆转了人类细胞的衰老时钟。该研究衍生了后续一系列通过部分重编程（partial reprogramming）技术进行衰老干预的探索，并在啮齿类动物模型中取得了重要进展。目前，部分重编程技术已成为实现器官和细胞更生的重要路径。病毒载体介导的重编程因子“疗法”在模式动物中显示出延缓器官退变的潜力。然而，基于重编程因子的细胞更生方案不可避免地存在擦除成体细胞分化状态、改变初始“细胞身份”（cell identity）、诱发肿瘤等风险。这在一定程度上限制了重编程技术在衰老干预中的临床应用前景。因此，领域内亟需发现独立于重编程因子的全新细胞更生因子，并据此发展更为安全、高效的衰老干预策略。 10月12日，动物所刘光慧研究组、曲静研究组，联合中国科学院北京基因组研究所张维绮课题组、任捷课题组，在《细胞-干细胞》（Cell Stem Cell）上，在线发表了题为Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation的研究论文。该研究首次通过基于人间充质前体细胞（human mesenchymal precursor cell，hMPC）的全基因组基因增强（Gain-of-function）筛选，鉴定出一系列促更生因子（rejuvenation factor）。其中，转录因子SOX5为筛选名单中全新、强效的更生因子，可通过靶向激活HMGB2的表达来重塑衰老细胞、重启细胞活力。更重要的是，基于SOX5过表达的“基因疗法”可以延缓小鼠关节衰老，促进关节软骨再生并改善骨关节炎症状。这为人类衰老相关疾病的防治提供了新的研究方向。科研人员基于该团队前期建立的人间充质前体细胞衰老研究体系，利用CRISPR激活（CRISPR activation，CRISPRa）工具介导的基因功能增强筛选技术，对全基因组范围内的两万多个蛋白编码基因进行全面排查，首次系统鉴定人间充质前体细胞的更生因子合集。通过对排名前列的强效更生因子开展独立功能分析，研究证实了这些因子的激活均可延缓人间充质前体细胞衰老，提示这个更生因子合集是一个值得挖掘的基因资源库。其中，转录因子SOX5与Yamanaka重编程因子SOX2属同一蛋白家族，且表现出显著的促细胞年轻化能力，因而成为研究关注的焦点。进一步，该研究通过多种技术手段、结合多种生理与病理性人类细胞衰老模型，证实SOX5可在不改变细胞身份的前提下促进人类细胞更生。为探讨更生背后的分子机制，研究通过表观和转录组学技术联合分析SOX5的作用靶点，发现了SOX5可作为转录激活因子结合于衰老抑制基因HMGB2增强子区域，从而激活HMGB2的表达，启动细胞年轻化进程。与之相对，抑制SOX5或HMGB2表达会加速细胞衰老。由此，该团队揭示了SOX5-HMGB2轴或可作为干预人类细胞衰老的关键靶标。研究通过在老年小鼠关节给予SOX5基因治疗验证其潜在应用价值。结果显示，SOX5基因治疗可有效延缓关节细胞衰老，抑制骨赘和滑膜增生，降低关节腔炎症水平并促进软骨再生。行为学实验进一步支持了上述成果即治疗组动物的肢体抓力显著提升。进而，该研究平行比较了SOX5基因治疗和Yamanaka四因子OSKM基因治疗在延缓骨关节炎方面的效果。两种处理在多项关节衰老的评价指标上效果相当，但由于SOX5单因子治疗不会引起细胞身份的改变，且SOX5单因子核酸编码序列较短，更易在细胞中均衡表达，因而在长期干预效果上可能具有更好的安全性和有效性。综上，基于SOX5的基因疗法或有望实现器官衰老的干预，助力延长健康寿命。该成果是合作团队于2021年明确人类全基因组衰老促进基因名录（Science Translational Medicine 2021）后，针对人类基因组中衰老抑制基因，首次系统筛选出SOX5等新型促更生因子。该研究加深了科学界对衰老程序化理论的认识，揭示了独立于重编程因子的全新细胞更生因子合集，并发展了逆转细胞和组织衰老的新型策略。这些新的知识和技术体系为阐明驱动衰老的分子通路、建立人类器官衰老及相关退行性疾病的临床诊断及干预手段提供了新可能。该研究由动物所、北京基因组所、北京干细胞与再生医学研究院、首都医科大学宣武医院等合作完成。研究工作得到科学技术部、国家自然科学基金委员会、中国科学院和北京市等的支持。研究揭示人类基因组中的“年轻化”基因

基因疗法

2022-08-17

·生物谷

研究揭示中华鳖精子发生紧密关联基因

精子发生是一个复杂的生理过程，爬行动物的精子发生与季节密切相关。中华鳖隶属的龟鳖目是四足动物中较古老的一类，在研究物种形态演化、生殖方式进化等领域具有独特的科研价值。近日，中国水产科学研究院珠江水产研究所龟鳖遗传育种创新团队在中华鳖精子发生分子机制的研究中取得系列进展。相关研究成果“expression and Characterization of theSpats1Gene and Its Response to E2/MT Treatment in the Chinese Soft-Shelled Turtle （Pelodiscus sinensis）”发表在《Animals》（IF2022=3.231, JCR一区），珠江所博士生雷骆和祝骏贤为共同第一作者，李伟副研究员和朱新平研究员为共同通讯；“The Seasonal and Stage?Specific expression Patterns ofHMGB2Suggest Its Key Role in Spermatogenesis in the Chinese Soft?Shelled Turtle （Pelodiscus sinensis）”发表在《Biochemical Genetics》（IF2022=2.220），珠江所副研究员李伟和博士生祝骏贤为共同第一作者，朱新平研究员为通讯作者。论文得到国家重点研发计划（2018YFD0900201）、国家自然科学基金青年项目（32102792）等的资助。精子发生是一个复杂的生理过程，爬行动物的精子发生与季节密切相关。中华鳖隶属的龟鳖目是四足动物中较古老的一类，在研究物种形态演化、生殖方式进化等领域具有独特的科研价值。中华鳖精子的发生具有季节依赖性，精子在春天开始产生，在夏天和秋天释放成熟精子，冬天精子产生不活跃。目前，有关中华鳖精子发生的研究大多集中在组织学层面，在分子水平上的研究较少。本次研究发现，中华鳖HMGB2mRNA在中华鳖睾丸中高表达，但在卵巢和其他组织中几乎未检测到。通过化学原位杂交发现，HMGB2mRNA在生殖细胞中特异表达，主要分布在圆形精子细胞和精子中。此外，HMGB2的相对表达与季节变化紧密相关。在4月和7月中，HMGB2转录本在睾丸中的表达呈上升趋势，并在7月达到峰值，10月后开始下降。结果表明，HMGB2与中华鳖的精子发生密切相关。相似的，Spats1在中华鳖中是一个雄性偏向基因，在睾丸中特异表达。Spats1的相对表达也与季节变化紧密关联。在夏季（7月）和秋季（10月），Spats1在睾丸中的表达显著高于其他季节。化学原位杂交发现Spats1mRNA在生殖细胞中特异表达，主要分布在初级精母细胞（Sc1）、次级精母细胞和精子（St）中。经17α-甲基睾酮（MT）和17β-雌二醇（E2）处理后孵化的稚鳖，尽管尾部都发生明显变化，但胚胎中Spats1的表达没有显著变化。在成体中，MT注射显著诱导雄性中华鳖Spats1的表达，E2注射对雄性中华鳖中Spats1的表达没有显著影响。这些结果均显示Spats1是一个雄性特异表达基因，与中华鳖的精子发生和释放密切相关。