Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
基本信息
- 批准号:8336243
- 负责人:
- 金额:$ 86.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:20q13AffectB-LymphocytesBindingCancer cell lineCell LineCellsChromatinChromatin LoopCodeCollaborationsDNADNA Binding DomainDNA MethylationDNA SequenceDevelopmentDistantDown-RegulationEnhancersEpigenetic ProcessExonsFingersFunctional RNAGene ExpressionGene TargetingGenesGeneticGenetic TranscriptionGerm CellsGoalsH19 geneHot SpotHumanHuman ChromosomesIndividualKnock-in MouseLeadLinkLymphoid CellMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMalignant neoplasm of testisMapsMediatingMethylationModelingMolecularMusOncogenesOvarianPAX5 genePathologicPatternPlayPrimary NeoplasmPropertyProtease GeneProteinsPublicationsRNA SplicingRegulationRegulatory ElementRoleSiteStructureSumSystemT-Cell LymphomaTERT geneTelomeraseTestingTestisTissuesTranscriptional ActivationTransfectionTransgenic OrganismsTranslational ResearchUterine CancerWorkbasecancer cellcell immortalizationclinical applicationembryonic stem cellfollow-upgenome-wideimmortalized cellimprintin vivolymph nodesmalemalignant breast neoplasmmodel developmentmutantnovelosteosarcomapaired box 5 protein (B-cell lineage specific activator)paralogous genepreventpromoterresearch studytumortumorigenesisvector
项目摘要
BORIS is a cancer/testis (CT) gene with the properties of a candidate oncogene and/or a cell-immortalizing gene. It maps to a cancer-associated hot spot on human chromosome 20q13 that shows frequent gains in copy number and/or amplification in a wide variety of human tumors. Similar to other CT, BORIS is aberrantly expressed in the majority of primary tumors and related cancer cell lines. As a CTCF- paralog, BORIS shares with CTCF a nearly identical 11 Zn-finger (11ZF) DNA binding domain (DBD), but their flanking NH2- and COOH-terminal regions are divergent. The 11ZF region was previously identified in the lab as a multivalent DBD, which is able to recognize and bind extended (around 50bp) target sequences. By virtue of sharing the identical DBD, CTCF and BORIS can recognize the same DNA sequences, but likely have distinct properties and form different associations with protein co-factors. Furthermore, due to the tissue-specific expression of BORIS in male germ cells, it is likely involved in re-establishment of paternal-specific DNA methylation patterns at particular imprinted sites of the Igf2/H19 locus through specific loop formation, by utilizing novel CTCF/BORIS sites. Based on our studies we predicted that most ICR sequences would contain meCpG-sensitive CTCF/BORIS target sites, which was validated for several unrelated imprinted loci. In addition to its role in development, BORIS likely plays a key role in oncogenesis. We and others characterized BORIS expression in uterine cancers, breast cancers, osteosarcomas, lung cancers, and prostate cancers. However, as BORIS is itself a gene expression regulator, it was hypothesized that BORIS-mediated regulation of promoters is the regulatory network responsible for the expression of multiple CT genes. Using the Boris KO model, we demonstrated that BORIS directly regulates the testis-specific protease gene TSP50, which is in turn negatively regulated by p53. We found that aberrant expression of both BORIS and TSP50 genes in cancers often coincide, suggesting the role of BORIS in activation of CT genes as downstream targets. In another line of experiments, we discovered that DNA methylation plays dual role in the regulation of human telomerase gene, hTERT, one of the key cell immortalization factors. Methylation prevents binding of CTCF, which has repressor activity, but partial hypomethylation of the core promoter is necessary for hTERT expression. In lymphoid cells, however, telomerase appears to be activated through a methylation-independent mechanism. In our follow-up work we found that in B cells, some T cell lymphomas, and in non-neoplastic lymph nodes, the hTERT promoter is unmethylated. The B cell-specific transcription factor PAX5 can override the repressive function of CTCF and activate hTERT in telomerase-positive B cells by a methylation-independent mechanism. The sum of recent studies suggests that that methylation per se is not the chief mechanism inhibiting CTCF binding at hTERT. We tested a hypothesis that abnormal activation of BORIS in cancer cells prevents CTCF binding to some key sites, including the hTERT promoter. Using human cancer cell lines where abnormal expression of BORIS was documented, as well as cells with transient expression of BORIS-coding vectors, we showed that BORIS binds the hTERT gene within the first exon and facilitates its transcription. Downregulation of BORIS led to a decrease of hTERT transcription in transient transfection experiments. However, in testicular and ovarian cell lines BORIS downregulation did not affect endogenous hTERT transcription. Thus, BORIS may play the role of CTCF antagonist, enabling the expression of hTERT in cancer and immortalized cells, but it is not a simple binary system.
BORIS是具有候选癌基因和/或细胞永生化基因的性质的癌症/睾丸(CT)基因。它映射到人类染色体20 q13上的癌症相关热点,该热点在各种人类肿瘤中显示出拷贝数和/或扩增的频繁增加。与其他CT类似,BORIS在大多数原发性肿瘤和相关癌细胞系中异常表达。作为CTCF的一个副产物,BORIS与CTCF共享一个几乎相同的11锌指(11 ZF)DNA结合结构域(DBD),但它们的侧翼NH 2-和COOH-末端区域是不同的。11 ZF区域先前在实验室中被鉴定为多价DBD,其能够识别并结合延伸的(约50 bp)靶序列。由于共享相同的DBD,CTCF和BORIS可以识别相同的DNA序列,但可能具有不同的特性,并与蛋白质辅因子形成不同的缔合。此外,由于BORIS在雄性生殖细胞中的组织特异性表达,它可能通过利用新的CTCF/BORIS位点,通过特异性环形成,参与在Igf 2/H19基因座的特定印迹位点处重建父系特异性DNA甲基化模式。基于我们的研究,我们预测大多数ICR序列将包含meCpG敏感的CTCF/BORIS靶位点,这在几个不相关的印迹基因座中得到了验证。除了在发育中的作用外,BORIS可能在肿瘤发生中起关键作用。我们和其他研究人员描述了BORIS在子宫癌、乳腺癌、骨肉瘤、肺癌和前列腺癌中的表达。然而,由于BORIS本身是一种基因表达调节剂,因此假设BORIS介导的启动子调节是负责多个CT基因表达的调节网络。使用Boris KO模型,我们证明了BORIS直接调节睾丸特异性蛋白酶基因TSP 50,而TSP 50又受p53负调控。我们发现,BORIS和TSP 50基因在癌症中的异常表达往往是一致的,这表明BORIS在激活作为下游靶点的CT基因中的作用。在另一系列实验中,我们发现DNA甲基化在人类端粒酶基因hTERT的调控中起双重作用,hTERT是细胞永生化的关键因子之一。甲基化阻止了CTCF的结合,CTCF具有阻遏活性,但是核心启动子的部分低甲基化对于hTERT表达是必需的。然而,在淋巴样细胞中,端粒酶似乎是通过甲基化非依赖性机制激活的。在我们的后续工作中,我们发现在B细胞、一些T细胞淋巴瘤和非肿瘤性淋巴结中,hTERT启动子未甲基化。B细胞特异性转录因子PAX 5可通过甲基化非依赖性机制克服CTCF的抑制功能并激活端粒酶阳性B细胞中的hTERT。最近的研究表明,甲基化本身不是抑制CTCF与hTERT结合的主要机制。我们测试了一个假设,即癌细胞中BORIS的异常激活阻止了CTCF与一些关键位点的结合,包括hTERT启动子。使用记录了BORIS异常表达的人类癌细胞系,以及具有BORIS编码载体的瞬时表达的细胞,我们表明BORIS在第一外显子内结合hTERT基因并促进其转录。在瞬时转染实验中,BORIS的下调导致hTERT转录的减少。然而,在睾丸和卵巢细胞系中,BORIS下调并不影响内源性hTERT转录。因此,BORIS可能发挥CTCF拮抗剂的作用,使hTERT在癌症和永生化细胞中表达,但它不是一个简单的二元系统。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Victor Lobanenkov其他文献
Victor Lobanenkov的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Victor Lobanenkov', 18)}}的其他基金
Regulation of CTCF Functions and Target Sites by Cancer/Testis-specific CTCF Like BORIS Factor
癌症/睾丸特异性 CTCF 样 BORIS 因子对 CTCF 功能和靶位点的调节
- 批准号:
10272128 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Regulation of CTCF Functions and Target Sites by Cancer/Testis-specific CTCF Like BORIS Factor
癌症/睾丸特异性 CTCF 样 BORIS 因子对 CTCF 功能和靶位点的调节
- 批准号:
10692106 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Deciphering CTCF code in mammalian host and viral epigenomes
破译哺乳动物宿主和病毒表观基因组中的 CTCF 代码
- 批准号:
10927769 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Regulation of CTCF Functions and Target Sites by Cancer/Testis-specific CTCF Like BORIS Factor
癌症/睾丸特异性 CTCF 样 BORIS 因子对 CTCF 功能和靶位点的调节
- 批准号:
10927815 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
- 批准号:
8946422 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
- 批准号:
9354824 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Normal and Pathologic Functions of CTCF and Its Distinct Classes of DNA-targets
CTCF 的正常和病理功能及其不同类型的 DNA 靶标
- 批准号:
8336142 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Normal and Pathologic Functions of CTCF and Its Distinct Classes of DNA-targets
CTCF 的正常和病理功能及其不同类型的 DNA 靶标
- 批准号:
7964430 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
- 批准号:
7964638 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
Normal and Pathologic Functions of CTCF and Its Distinct Classes of DNA-targets
CTCF 的正常和病理功能及其不同类型的 DNA 靶标
- 批准号:
8745378 - 财政年份:
- 资助金额:
$ 86.88万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 86.88万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 86.88万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 86.88万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 86.88万 - 项目类别:
Grant-in-Aid for Early-Career Scientists