RFX6

更新于：2025-05-07

基本信息

别名

dJ955L16.1、DNA-binding protein RFX6、MGC33442

+ [5]

简介

Transcription factor required to direct islet cell differentiation during endocrine pancreas development. Specifically required for the differentiation of 4 of the 5 islet cell types and for the production of insulin (PubMed:20148032, PubMed:25497100). Not required for pancreatic PP (polypeptide-producing) cells differentiation. Acts downstream of NEUROG3 and regulates the transcription factors involved in beta-cell maturation and function, thereby restricting the expression of the beta-cell differentiation and specification genes, and thus the beta-cell fate choice. Activates transcription by forming a heterodimer with RFX3 and binding to the X-box in the promoter of target genes (PubMed:20148032). Involved in glucose-stimulated insulin secretion by promoting insulin and L-type calcium channel gene transcription (PubMed:25497100).

关联

100 项与 RFX6 相关的临床结果

登录后查看更多信息

100 项与 RFX6 相关的转化医学

登录后查看更多信息

0 项与 RFX6 相关的专利（医药）

登录后查看更多信息

108

项与 RFX6 相关的文献（医药）

2025-05-01·Journal of Applied Genetics

Unraveling the genetic basis of MODY: insights from next-generation sequencing

Article

作者: Eser, Metin ; Hekimoglu, Gulam ; Dursun, Fatma

Maturity-onset diabetes of the young (MODY) is an uncommon kind of monogenic diabetes. The major characteristics of MODY include not having insulin resistance and the absence of autoimmunity, early onset, and a family history suggesting autosomal-dominant inheritance. Nonetheless, genetic testing is necessary for diagnosis. The MODY-related genes CEL, ABCC8, PDX1, GCK, WFS1, HNF4A, HNF1A, and HNF1B were examined using Next Generation Sequencing (NGS) in this investigation. This study aimed to evaluate the genetic and clinical characteristics of patients referred with a preliminary diagnosis of MODY, retrospectively. A total of 30 patients (18 male and 12 female) participated, with ages ranging from 5 to 56. Eight distinct genetic variants were identified in 17 cases (57%). Pathogenic variants in the HNF1A gene have been identified. Likely pathogenic variants were found in CEL, ABCC8, GCK, and HNF4A. The genes APPL1, BLK, INS, KCNJ1, KLF11, NEUROD1, PAX4, RFX6, and ZFP57 were shown to be mutation-free. Four distinct pathogenic variants are found in this series. Unexpectedly high rates of pathogenic variants have been found in the HNF1A gene. In 27% of cases, there is a family history of vertically transmitted diabetes. The study highlights the importance of genetic testing for individuals with early-onset diabetes and a strong family history of the condition. Comprehensive genetic testing and increased public awareness are essential for MODY.

2024-12-01·Diabetologia

Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1+/NKX6.1+ progenitors

Article

作者: Hayat, Sikander ; Memon, Bushra ; Ijaz, Sadaf ; Abdelalim, Essam M ; Aldous, Noura ; Elsayed, Ahmed K

AbstractAims/hypothesisHomozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6’s known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6.MethodsWe examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs).ResultsRFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets.Conclusions/interpretationThese findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes.Data availabilityRNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891).Graphical Abstract

2024-09-18·JCEM Case Reports

Partial Lipodystrophy Affecting the Extremities in a Young Woman With Autoimmune Polyglandular Syndrome 1

Article

作者: Garg, Abhimanyu ; Anderson, Mark S ; Bodansky, Aaron ; Agarwal, Shubham ; Xing, Chao

AbstractAutoimmune polyglandular syndrome 1 (APS1) is an autosomal recessive disorder due to biallelic pathogenic variants in the autoimmune regulator (AIRE) gene that manifests with chronic mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. We report a 39-year-old woman with APS1 who developed partial lipodystrophy during adulthood. She presented with diaper rashes, oral thrush, and tetany during infancy due to candidiasis and hypoparathyroidism. During childhood, she developed hypothyroidism, primary adrenal insufficiency, and ovarian insufficiency.At age 14, she received a sibling-matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At age 35, her serum triglycerides were 914 mg/dL (10.32 mmol/L) and she had loss of subcutaneous fat from the upper and lower extremities and hips. A whole-body dual-energy x-ray absorptiometry revealed lower-extremity fat at less than the first percentile. Whole-exome sequencing on DNA extracted from saliva revealed pathogenic variants, p.Leu28Pro and p.Arg257* in AIRE but none in the known lipodystrophy genes. Phage-immunoprecipitation-sequencing revealed the presence of autoantibodies to MAGEB1, MAGEB4, and RFX6, which have been previously reported in APS1. Our case suggests that patients with APS1 may develop partial lipodystrophy due to autoantibodies against novel adipocyte-expressed proteins. A causal relationship of high levels of autoantibodies in our patient to adipose tissue–expressed ODC1, NUCKS1, or FNBP1L and lipodystrophy remains uncertain.

项与 RFX6 相关的新闻（医药）

2024-10-05

·生物探索

EMBO J | 周兆才/焦石/安利伟发现辅因子介导的基因转录抑制性相分离现象并研发诱导TEAD4抑制性相分离的抗肿瘤干预策略

引言相分离是生物大分子在特定状态下的一种特殊的自发凝聚现象，在基因转录、表观遗传、信号转导等细胞正向生长过程中发挥关键调节作用，但目前对于生物大分子在肿瘤等乏营养背景下相分离现象及其功能作用仍缺乏了解，阻碍了靶向相分离相关的抗肿瘤干预策略的研发。 2024年10月2日，复旦大学周兆才/焦石及同济大学附属第十人民医院安利伟联合团队在EMBO J上发表了文章A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis。该研究首次发现了一种由葡萄糖剥夺引起的与抑制基因转录相关的生物大分子相分离现象，并以Hippo信号通路下游的转录因子TEAD4为例，鉴定了调控其抑制性相分离的辅助因子并解释其对基因转录调控的分子机制，并研发了基于多肽的靶向诱导TEAD4抑制性相分离的抗肿瘤干预策略。该团队前期系统性地研究了Hippo信号通路的调控网络和分子机制，探究了其在胃肠道肿瘤发生过程中的病理作用，发现了YAP拮抗蛋白VGLL4以及激活蛋白IRF3等调控肿瘤发生发展的功能与机制，并设计发展了靶向抗癌的治疗性多肽及小分子化合物（Cancer Cell 2014/2020; Cell Res 2014; Nat Commun 2017; J Exp Med 2018）。为了探究乏营养等肿瘤特征对转录因子相分离的调节效应，该团队利用高内涵成像对超过700多个转录因子的文库进行不同条件的系统筛选，发现葡萄糖剥夺可诱导包括TEAD4, EWSH、RFXDC1、GTF2A1L、C16orf5、ZNF800和ELF1等多个转录因子形成生物大分子凝聚体，且这些相分离与转录抑制性表观修饰如H3K27me3存在明显共定位，因此把这一现象命名为转录因子的抑制性相分离现象（Repressive TF condensation）。在此基础上，该团队以TEAD4为例，发现VGLL4和RFXANK等辅因子可以介导TEAD4的寡聚并促进抑制型相分离生成。与前期已知的YAP/TAZ介导的TEAD4转录激活相分离相比，本研究揭示的TEAD4抑制型相分离可导致DNA/染色质聚集和缠绕从而触发细胞死亡。受此启发，该团队结合前期解析的VGLL4-TEAD4晶体结构，创造性设计了一个模拟VGLL4与TEAD4结合基序衍生肽（GLUP）。体内外实验发现该GLUP多肽能够特异性诱导TEAD4抑制性相分离发生，进而抑制基因转录和细胞生长，在遗传和异种移植胃癌小鼠模型中显示出很强的抗肿瘤作用。模式图（Credit: EMBO J）该研究的发现揭示了生物大分子相分离对细胞生长调控的新型模式和分子机制，为靶向相分离的肿瘤治疗提供新思路。同时，这项研究创新性地围绕调控转录因子相分离类型抗肿瘤药物的设计，诱导抑制型相分离，为肿瘤发生的病理机制及靶向干预策略提供了新的策略和先导药物。参考文献 https://doi.org/10.1038/s44318-024-00257-4 责编|探索君排版|探索君文章来源|“BioArt” 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

临床结果

2023-12-22

·今日头条

新型癌症驱动因子！中山大学发文：肝细胞癌最新进展机制

本文为转化医学网原创，转载请注明出处作者：Rainbow 导读：肝细胞癌（HCC）是导致癌症相关死亡的重要因素，在全球排名第三。近日，中山大学研究团队在期刊《CLINICAL AND TRANSLATIONAL MEDICINE》上在线发表题为“RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1”的研究论文，研究表明， RFX6是肿瘤发展的一个重要基因，并揭示了它对肝细胞癌（HCC）进展的影响。研究首次揭示了RFX6对糖酵解的影响，并进一步证明了这种新型RFX6-PGAM1调节轴在HCC进展中的重要性。研究可能为HCC提供一个新的治疗靶点。 https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1511 研究背景 01 肝细胞癌（HCC）是导致癌症相关死亡的重要因素，在全球排名第三。大多数HCC病例被诊断出有多个肿瘤（n>3）、血管侵犯或远处转移，留下了几种治愈的选择。尽管癌症治疗取得了进展，但目前对于HCC的治疗选项有限，有必要理解HCC发展的分子机制并确定特定的新治疗靶点。调节因子X6（RFX6）是一种具有翅膀螺旋转录因子的蛋白，属于高度保守的DNA结合蛋白家族——调节因子X（RFX）家族。RFX6在胰岛中表达，并且对于胰岛细胞分化至关重要。需要进一步详细的研究来阐明其在HCC中的确切作用。磷酸甘油酸变位酶1（PGAM1）是一种重要的糖酵解酶，在本研究中被确定为RFX6的下游靶点之一。最近的研究表明，在包括HCC在内的各种癌症中，PGAM1的异常表达与不良临床结果相关，这暗示了PGAM1在癌症发展中的潜在作用。它还与DNA双链断裂修复有关。除了葡萄糖代谢外，这种糖酵解酶还通过调节肌动蛋白丝的组装加剧了癌细胞的迁移。因此，PGAM1可能主要介导了RFX6在HCC中的促肿瘤功能。在体外和体内过表达RFX6促进了肝细胞癌细胞的增殖和迁移能力 02 为了验证RFX6的生物功能，研究人员选择了Huh7和MHCC-97H细胞构建稳定的RFX6过表达细胞。与对照组相比，RFX6过表达组显示出增强的细胞增殖能力。转移试验显示RFX6过表达增加了HCC细胞的运动能力。在皮下肿瘤模型中，RFX6过表达组的肿瘤体积和重量均大于对照组。在随后构建的同种异体移植模型中，RFX6过表达组显示出比对照组更大的肿瘤负担。肿瘤组织的免疫组织化学染色还显示出RFX6过表达组Ki67阳性细胞数增加。在体内肺转移模型中，RFX6过表达组检测到增加的荧光素信号和转移结节数。这些结果表明，RFX6过表达在体内外均增强了HCC细胞的增殖和运动能力。研究结果 03 综上所述，研究表明， RFX6是肿瘤发展的一个重要基因，并揭示了它对肝细胞癌（HCC）进展的影响。研究首次揭示了RFX6对糖酵解的影响，并进一步证明了这种新型RFX6-PGAM1调节轴在HCC进展中的重要性。研究可能为HCC提供一个新的治疗靶点。参考资料： https://onlinelibrary.wiley.com/doi/10.1002/ctm2.1511 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

2023-12-05

·奇点网

《自然》重磅：2型糖尿病起点，找到了！科学家汇总2型糖尿病的数百个风险基因，找到驱动疾病的核心枢纽丨科学大发现

*仅供医学专业人士阅读参考2型糖尿病（T2D）已经成了一个全社会的健康问题，越来越多的年轻人得上了前驱性糖尿病。糖尿病听起来好像不致命，但它增加了失明、肾衰、心脏病等多种并发症风险，实乃人类健康的一大威胁。2型糖尿病到底是怎么来到我们身边的？近日，范德比尔特大学和密歇根大学的科研团队在《自然》杂志发文，研究者们整合了多种分析方法，发现2型糖尿病的数百个相关基因位点可以被划分为特定功能的基因组，它们共同调控2型糖尿病的发生，导致早期疾病标志β细胞功能受损。在这个庞大的基因调控网络中，研究者找到了核心枢纽RFX6，它的表达减少与β细胞功能缺陷有关。令人兴奋的是，这种分析方法也可以同样应用于其他疾病，为我们识别疾病的基因调控网络提供了灯塔。论文题图2型糖尿病是一种相对复杂的疾病，涉及影响多种分子途径和组织的遗传、环境和病生理要素。科学家也尝试从基因角度寻找2型糖尿病的根源，通过全基因组关联研究（GWAS）已经确定了400多个相关信号，而其中90%的单核苷酸多态性（SNPs）位于非编码基因的增强子区域，可能参与调控β细胞和胰岛细胞特异性的基因表达。由此可见，β细胞过程应当在2型糖尿病病生理中占据决定性的地位。实验结果也的确如此。研究者们收集了早期2型糖尿病患者的胰腺和胰岛进行多模式分析，与健康对照组相比，T2D胰岛的基础胰岛素分泌相似，但在高葡萄糖等条件刺激下的胰岛素分泌显著减少。与之相反，T2D胰岛的胰高血糖素分泌则比较正常。这些结果强调，β细胞的失调是驱动胰岛素减少的关键特征。实验流程而β细胞发生的问题，并不在于数量。经研究者分析，早期T2D中内分泌细胞群和β细胞的质量变化并不关键，胰岛素分泌减少应当是β细胞本身的功能出现了障碍。为了寻找出β细胞功能障碍的关键基因，研究者对α细胞、β细胞、胰岛样本进行了加权基因共表达网络分析（WGCNA），将相关的特征基因归类到不同模块，在转录组、供体特征、胰岛功能参数和基因之间建立关联。WGCNA结果研究者在网站上公开了WGCNA的结果（https://theparkerlab.shinyapps.io/Islet-RNAseq-WGCNA/），并提出了一些可能具有临床价值的观察，在此不再赘述。β细胞调控涉及如此复杂的基因网络，其中有没有角色特别重要的关键“人物”呢？研究者尝试筛选了网络中表达与模块内部和跨模块的其他基因高度相关的枢纽基因，发现RFX6非常符合标准。RFX6本就与单基因和多基因糖尿病有关，它在β细胞中相关性最强的转录因子之一，且在2型糖尿病中转录减少。实验结果显示，敲低β细胞中的RFX6会导致广泛的转录和染色质变化，与GWAS中2型糖尿病相关调控元件的破坏有关。研究者还利用英国生物库这个大型队列进行了人群水平研究，通过孟德尔分析确认了在欧洲血统中RFX6与2型糖尿病之间的因果关系。孟德尔分析显示在欧洲血统中RFX6与2型糖尿病有因果关系总的来说，这项研究将β细胞功能受损定义为早期2型糖尿病的标志，并在基因调控网络中寻找到了关键的枢纽转录因子RFX6，它在β细胞中的表达减少与葡萄糖刺激导致的胰岛素分泌减少有关。那么接下来的问题就是，最初的RFX6失调又是如何发生的呢？RFX6在胰岛细胞发育和功能维持中又保守作用，研究者认为，它的失衡可能是环境、营养、年龄相关的应激因素叠加后的体现。能否找到初始事件，以及它是否能够靶向以预防或逆转β细胞的功能缺陷，是接下来的课题。参考资料：[1]Walker, J.T., Saunders, D.C., Rai, V. et al. Genetic risk converges on regulatory networks mediating early type 2 diabetes. Nature (2023). https://doi.org/10.1038/s41586-023-06693-2[2]https://news.vumc.org/2023/12/04/study-links-gene-network-and-pancreatic-beta-cell-defects-to-type-2-diabetes/本文作者丨代丝雨

细胞疗法