WO2017036052A1 - Recombinant promoter regulated by retinoic acid with concentration dependent effect and use thereof - Google Patents
Recombinant promoter regulated by retinoic acid with concentration dependent effect and use thereof Download PDFInfo
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- the invention belongs to the field of medical biotechnology research and relates to a recombinant promoter with concentration-dependent effect regulated by retinoic acid.
- the promoter is composed of a regulatory box A and a control box B, and the control box A comprises 10 DR5 elements. (5'-GTTCAC-3') is composed in series, and the control box B is a 115 bp artificially designed assisted starting element.
- the reporter gene linked to the recombinant promoter can be used to display and detect the concentration level of retinoids in the extracellular fluid or environment; the recombinant promoter can be used to regulate the expression of the gene of interest in cells or animals in vitro; Recombinant promoters can also be used to regulate the expression of therapeutic genes in human gene therapy.
- a retinoic acid response element exists in the genome of a natural organism, and the retinoic acid response element is generally present in the upstream sequence of the gene regulatory promoter in two to four repeating arrangements.
- the retinoid response element in conjunction with other transcription factor regulatory elements, collectively regulates the transcriptional expression of downstream genes.
- the base sequence composition of the retinoic acid response element generally has multiple types, which are named DR1, DR2, DR3, DR4 and DR5 elements, respectively.
- RAR and RXR form a heterodimer, they recognize the retinoic acid response element on the genome and bind to it.
- the retinoic acid enters the nucleus and binds to RAR/RXR. The expression of downstream genes is initiated.
- the retinoic acid-RAR/RXR needs to work in concert with other transcription factors (such as NF- ⁇ B or STAT) to initiate downstream genes. expression.
- retinoic acid-regulated promoter there is no concentration-dependent retinoic acid-regulated promoter in nature.
- Previous researchers have attempted to construct a retinoic acid-regulated promoter with a concentration-dependent effect, but they are not perfect.
- Jason Aoto et al.1 constructed a retinoic acid-regulated promoter consisting of 6 DR5 elements and a thymidine.
- the kinase promoter (Thymidine Kinase, TK promoter, 750 bp) is composed.
- Figure 3C published by the author, it is clear that EGFP still has a distinct background expression in the absence of retinoic acid. .
- thymidine kinase promoter as a co-promoter element, and the thymidine kinase promoter itself has independent transcriptional activity in retinoic acid. In the absence of -RAR/RXR, the expression of downstream genes can still be initiated.
- a retinoic acid-regulated promoter with a concentration-dependent effect was invented (ie, when the retinoic acid was not added, the downstream gene was not expressed, and as the concentration of retinoic acid increased, the downstream gene gradually increased the expression level), not only for in vitro experimental studies. It is a good gene regulation tool, and it is also a new therapeutic gene regulation method for gene therapy in vivo.
- the present invention is based on the recombination of DR5 elements, using a series of 10 DR5 elements in series to form a control box A, the base sequence of which is as follows:
- the control box B is a 115 bp artificially designed assisted activation element whose base sequence is as follows:
- the complete base sequence of the promoter is as follows:
- the invention also discloses a method for applying a recombinant promoter having a concentration-dependent effect regulated by retinoic acid.
- the promoter-linked green fluorescent protein or luciferase reporter gene has a method for detecting and detecting trace levels of retinoic acid in an extracellular fluid or environment, and is a method for detecting a retinoid.
- a retinoid drug such as all-trans retinoic acid
- a retinoid drug is added to regulate the expression of the target gene, which is used to regulate the expression of the target gene in cells or animals in vitro.
- intravenous or oral retinoids (such as all-trans retinoic acid) regulate the expression of therapeutic genes, which are used to regulate therapeutic gene expression in human gene therapy.
- the present invention also indicates that the promoter can be used to regulate the expression of the T cell chimeric antigen receptor (CAR-T) gene and avoid the formation of cytokine storms.
- CAR-T T cell chimeric antigen receptor
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Abstract
Description
本发明属于医学生物技术研究领域，涉及一种受维甲酸调控的具有浓度依赖效应的重组启动子，具体为该启动子由调控盒A和调控盒B组成，调控盒A包含有10个DR5元件(5’-GTTCAC-3’)串联组成，调控盒B为115bp人工设计的协助启动元件。该重组启动子链接的报告基因能够用于显示及检测细胞外液或环境中维甲酸类药物的浓度水平；该重组启动子能够用于体外细胞内或动物中调控目的基因的表达；另外，该重组启动子还能够用于人体基因治疗中调控治疗基因的表达。The invention belongs to the field of medical biotechnology research and relates to a recombinant promoter with concentration-dependent effect regulated by retinoic acid. Specifically, the promoter is composed of a regulatory box A and a control box B, and the control box A comprises 10 DR5 elements. (5'-GTTCAC-3') is composed in series, and the control box B is a 115 bp artificially designed assisted starting element. The reporter gene linked to the recombinant promoter can be used to display and detect the concentration level of retinoids in the extracellular fluid or environment; the recombinant promoter can be used to regulate the expression of the gene of interest in cells or animals in vitro; Recombinant promoters can also be used to regulate the expression of therapeutic genes in human gene therapy.
自然界生物的基因组中存在一种维甲酸反应元件(retinoic acid response elements，RARE)，该维甲酸反应元件一般以2～4个重复排列的形式存在于基因调控启动子的上游序列中。该维甲酸反应元件会联合其它转录因子调控元件共同调控下游基因的转录表达。A retinoic acid response element (RARE) exists in the genome of a natural organism, and the retinoic acid response element is generally present in the upstream sequence of the gene regulatory promoter in two to four repeating arrangements. The retinoid response element, in conjunction with other transcription factor regulatory elements, collectively regulates the transcriptional expression of downstream genes.
维甲酸反应元件的碱基序列组成一般有多个类型，分别命名为DR1、DR2、DR3、DR4和DR5元件。细胞内转录因子RAR和RXR形成异源二聚体后，会识别基因组上的维甲酸反应元件与之结合，当细胞摄入维甲酸类药物后，维甲酸进入细胞核内与RAR/RXR结合，从而启动下游基因的表达。The base sequence composition of the retinoic acid response element generally has multiple types, which are named DR1, DR2, DR3, DR4 and DR5 elements, respectively. When the intracellular transcription factors RAR and RXR form a heterodimer, they recognize the retinoic acid response element on the genome and bind to it. When the cells ingest the retinoid, the retinoic acid enters the nucleus and binds to RAR/RXR. The expression of downstream genes is initiated.
然而，在自然界中并不存在单一的受维甲酸反应元件调控的启动子，也就是说，维甲酸-RAR/RXR需要协同其它转录因子(如NF-κB或STAT)共同作用，才能启动下游基因的表达。However, there is no single promoter regulated by the retinoid response element in nature, that is, the retinoic acid-RAR/RXR needs to work in concert with other transcription factors (such as NF-κB or STAT) to initiate downstream genes. expression.
另外，自然界中也不存在具有浓度依赖效应的维甲酸调控启动子。以往的科研工作者试图构建具有浓度依赖效应的维甲酸调控启动子，但是都很不完美，如Jason Aoto等1构建了一种维甲酸调控启动子，它是由6个DR5元件和一个胸苷激酶启动子(Thymidine Kinase，TK promoter，750bp)组成，然而在该作者发表文章的Figure 3C中，可以清楚地看出，在没有维甲酸存在的情况下，EGFP仍然有一个很明显的本底表达。这是因为该作者使用了胸苷激酶启动子做为协同启动子元件，胸苷激酶启动子本身就具有独立的转录活性，在维甲酸 -RAR/RXR不存在的情况下，依旧能启动下游基因的表达。In addition, there is no concentration-dependent retinoic acid-regulated promoter in nature. Previous researchers have attempted to construct a retinoic acid-regulated promoter with a concentration-dependent effect, but they are not perfect. For example, Jason Aoto et al.1 constructed a retinoic acid-regulated promoter consisting of 6 DR5 elements and a thymidine. The kinase promoter (Thymidine Kinase, TK promoter, 750 bp) is composed. However, in Figure 3C published by the author, it is clear that EGFP still has a distinct background expression in the absence of retinoic acid. . This is because the author uses the thymidine kinase promoter as a co-promoter element, and the thymidine kinase promoter itself has independent transcriptional activity in retinoic acid. In the absence of -RAR/RXR, the expression of downstream genes can still be initiated.
因此，发明一个具有浓度依赖效应的维甲酸调控启动子(即在不加入维甲酸时，下游基因不表达，而随着维甲酸浓度的增加，下游基因逐步提高表达水平)，不仅对于体外实验研究是一个很好的基因调控工具，而且对于体内基因治疗来说，也是一个新的治疗基因的调控手段。Therefore, a retinoic acid-regulated promoter with a concentration-dependent effect was invented (ie, when the retinoic acid was not added, the downstream gene was not expressed, and as the concentration of retinoic acid increased, the downstream gene gradually increased the expression level), not only for in vitro experimental studies. It is a good gene regulation tool, and it is also a new therapeutic gene regulation method for gene therapy in vivo.
1.Aoto J,Nam CI,Poon MM,Ting P,Chen L.Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity.Neuron.2008Oct 23；60(2):308-20.doi:10.1016/j.neuron.2008.08.012。1.Aoto J, Nam CI, Poon MM, Ting P, Chen L. Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron. 2008 Oct 23; 60 (2): 308-20. doi: 10.1016/j. Neuron.2008.08.012.
发明内容Summary of the invention
本发明是基于通过对DR5元件的重新组合，串联使用了数量为10个的DR5元件，组成了调控盒A，其碱基序列如下：The present invention is based on the recombination of DR5 elements, using a series of 10 DR5 elements in series to form a control box A, the base sequence of which is as follows:
然而，这10个DR5元件组成的调控盒A是无法高效启动下游基因的表达。调控盒A需要协助启动元件调控盒B这一顺式反应元件才能高效地启动下游基因的表达。调控盒B为一个长度为115bp人工设计的协助启动元件，该元件的碱基序列如下：However, the regulatory cassette A consisting of these 10 DR5 elements was unable to efficiently initiate expression of downstream genes. Regulatory cassette A needs to assist in the initiation of the elemental regulatory element B, a cis-responsive element to efficiently initiate expression of downstream genes. The control box B is a 115 bp artificially designed assisted activation element whose base sequence is as follows:
调控盒A和调控盒B共同组成了受维甲酸调控的具有浓度依赖效应的重组启动子，该启动子的完整碱基序列如下：The regulatory cassette A and the regulatory cassette B together constitute a concentration-dependent recombinant promoter regulated by retinoic acid. The complete base sequence of the promoter is as follows:
长度为297bp的受维甲酸调控的具有浓度依赖效应的重组启动子，在297碱基位 置后直接链接下游基因ORF的起始密码子ATG，在维甲酸-RAR/RXR存在的情况下，就能够启动目的基因的表达。a 297 bp recombinant promoter with a concentration-dependent effect regulated by retinoic acid at 297 base positions The initial codon ATG of the downstream gene ORF is directly linked, and in the presence of retinoic acid-RAR/RXR, the expression of the gene of interest can be initiated.
本发明还公开了受维甲酸调控的具有浓度依赖效应的重组启动子的应用方法。该启动子链接的绿色荧光蛋白或荧光素酶等报告基因，具有显示及检测细胞外液或环境中维甲酸类药物的痕量浓度水平，是一种检测维甲酸类药物的方法。The invention also discloses a method for applying a recombinant promoter having a concentration-dependent effect regulated by retinoic acid. The promoter-linked green fluorescent protein or luciferase reporter gene has a method for detecting and detecting trace levels of retinoic acid in an extracellular fluid or environment, and is a method for detecting a retinoid.
该启动子链接的目的基因进入细胞核后，加入维甲酸类药物(如全反式维甲酸)，以此来调控目的基因的表达，是一种在体外细胞内或动物中用于调控目的基因表达的方法。After the target gene linked by the promoter enters the nucleus, a retinoid drug (such as all-trans retinoic acid) is added to regulate the expression of the target gene, which is used to regulate the expression of the target gene in cells or animals in vitro. Methods.
该启动子链接的治疗基因整合入宿主基因组后，静脉或口服维甲酸类药物(如全反式维甲酸)来调控治疗基因的表达，是一种在人体基因治疗中用于调控治疗基因表达的方法。After the promoter-linked therapeutic gene is integrated into the host genome, intravenous or oral retinoids (such as all-trans retinoic acid) regulate the expression of therapeutic genes, which are used to regulate therapeutic gene expression in human gene therapy. method.
本发明还指出该启动子可以用于调控T细胞嵌合抗原受体(CAR-T)基因的表达，避免细胞因子风暴的形成。The present invention also indicates that the promoter can be used to regulate the expression of the T cell chimeric antigen receptor (CAR-T) gene and avoid the formation of cytokine storms.
图1.在huh7细胞中转染重组启动子链接的绿色荧光蛋白报告基因，在培养液中加入全反式维甲酸(浓度为10-8M)，24小时后用荧光显微镜(Olympus IX-71)拍摄，huh7细胞中无绿色荧光蛋白表达。Figure 1. Green fluorescent protein reporter gene transfected with recombinant promoter in huh7 cells, all-trans retinoic acid (concentration 10 -8 M) was added to the culture medium, and fluorescence microscope (Olympus IX-71) was used 24 hours later. ), no green fluorescent protein was expressed in huh7 cells.
图2.在huh7细胞中转染重组启动子链接的绿色荧光蛋白报告基因，在培养液中加入全反式维甲酸(浓度为10-7M)，24小时后用荧光显微镜(Olympus IX-71)拍摄，huh7细胞中见少量绿色荧光蛋白表达。Figure 2. Green fluorescent protein reporter gene transfected with recombinant promoter in huh7 cells, all-trans retinoic acid (concentration 10 -7 M) was added to the culture medium, and fluorescence microscope (Olympus IX-71) was used 24 hours later. ), a small amount of green fluorescent protein was observed in huh7 cells.
图3.在huh7细胞中转染重组启动子链接的绿色荧光蛋白报告基因，在培养液中加入全反式维甲酸(浓度为10-6M)，24小时后用荧光显微镜(Olympus IX-71)拍摄，huh7细胞中见大量绿色荧光蛋白表达。 Figure 3. Green fluorescent protein reporter gene transfected with recombinant promoter in huh7 cells, all-trans retinoic acid (concentration 10 -6 M) was added to the culture medium, and fluorescence microscope (Olympus IX-71) was used 24 hours later. ), a large amount of green fluorescent protein expression was observed in huh7 cells.
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| CN201510539568.5A CN106480024B (en) | 2015-08-30 | 2015-08-30 | Recombinant promoter with concentration-dependent effect regulated by retinoic acid and its use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991007488A1 (en) * | 1989-11-16 | 1991-05-30 | The Salk Institute For Biological Studies | Beta retinoic acid response elements compositions and assays |
| WO1992016658A1 (en) * | 1991-03-18 | 1992-10-01 | The Salk Institute For Biological Studies | Response element compositions and assays employing same |
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| US5922596A (en) * | 1990-12-10 | 1999-07-13 | Bristol-Myers Squibb Co. | Promoter of the retinoic acid receptor gene for directing gene expression |
| FR2732035B1 (en) * | 1995-03-23 | 1997-05-30 | Agronomique Inst Nat Rech | METHOD FOR REGULATING THE EXPRESSION OF A GENE IN A BACULOVIRUS, BY A FIXATION SITE OF A RETINOIC ACID RECEPTOR, AND VECTOR FOR CARRYING OUT SAID METHOD |
| CA2383698A1 (en) * | 1999-09-01 | 2001-03-08 | Bristol-Myers Squibb Company | In vitro transcription systems and uses |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991007488A1 (en) * | 1989-11-16 | 1991-05-30 | The Salk Institute For Biological Studies | Beta retinoic acid response elements compositions and assays |
| WO1992016658A1 (en) * | 1991-03-18 | 1992-10-01 | The Salk Institute For Biological Studies | Response element compositions and assays employing same |
Non-Patent Citations (2)
| Title |
|---|
| AOTO, J. ET AL.: "Synaptic Signaling by All-Trans Retinoic Acid in Homeostatic Synaptic Plasticity", NEURON, vol. 60, no. 2, 23 October 2008 (2008-10-23), pages 308 - 320, XP055365143, ISSN: 0896-6273 * |
| SUN, YUQIANG ET AL.: "Advanced Progress on The Relationship Between RA and Its Receptors and Malignant Tumors", CHINESE BULLETIN OF LIFE SCIENCE, vol. 26, no. 3, 15 March 2014 (2014-03-15), pages 295 - 301, ISSN: 1004-0374 * |
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