Intron Retention Mechanisms that Regulate Erythroid SF3B1 Gene Expression
调节红细胞 SF3B1 基因表达的内含子保留机制
基本信息
- 批准号:9307813
- 负责人:
- 金额:$ 35.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AchievementAddressAntisense OligonucleotidesAutomobile DrivingBinding ProteinsCell Differentiation processCell ProliferationCellsDataDefectDevelopmentDiseaseDistalDistantDysmyelopoietic SyndromesElementsEngineeringEnhancersErythroblastsErythroidErythropoiesisEventExcisionExhibitsExonsFutureGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGoalsHematological DiseaseHematologyHomeostasisHumanIntronsInvestigationIronLeadLengthManuscriptsMediatingMessenger RNAMetal Ion BindingMethodsMissionMitochondriaModelingMolecularMutationMutation AnalysisNIH Program AnnouncementsNational Institute of Diabetes and Digestive and Kidney DiseasesOligonucleotidesOrthochromatophilic ErythroblastOutputPatientsPatternPlayPositioning AttributeProcessPronormoblastsProteinsRNARNA ProcessingRNA SplicingReagentRegulationRegulator GenesRegulatory ElementReporterRepressionResearchRoleSiteSpecificityStructureSyndromeTechniquesTechnologyTestingTherapeuticTranscriptTranscription ProcessUp-Regulationbasedeletion analysisdesignexperienceexperimental studyhuman diseaseinsightmembernovelparalogous geneprogramsresponsetherapy designtranscriptometreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
This SHINE II proposal will address a novel mechanism of gene regulation, intron retention (IR), as it applies to
a major splicing regulator / blood disease gene (SF3B1), and an iron homeostasis gene, SLC25A28
(mitoferrin-2). These gene models represent developmentally dynamic and developmentally stable retention
events, respectively, that likely are regulated by different mechanisms. Goals of this proposal are to define the
mechanism(s), and to obtain proof of principle that this mechanistic information can lead to methods for
modulation of retention in a potentially therapeutic manner. IR transcripts, which by definition retain at least
one unspliced intron, represent an abundant fraction of many genes' transcriptional output in human
erythroblasts: up to 50% in both SF3B1 and SLC25A37 (mitoferrin-1). The latter is a close paralog of
SLC25A28 and is very highly expressed in late erythroblasts, but SLC25A28 is more amenable to study due to
smaller intron size. IR can theoretically impose major post-transcriptional limits on expression of translatable
mRNA during normal development, and by extension mis-regulated could effect quantitative abnormalities of
expression in putative `intron retention' diseases. Indeed, aberrant intron retention is a hallmark of myelo-
dysplasia syndrome (MDS) in patients with ZRSR2 mutations. Little is known about molecular mechanisms
controlling IR. IR in SF3B1 is developmentally dynamic, being up-regulated from 20% to 50% as cells mature
from proerythroblasts (lower IR) to orthochromatophilic erythroblasts (higher IR). One model for IR regulation
in this gene involves activity of `decoy' or `cryptic' exons in the intron that may interact with the flanking splice
sites to block intron excision. In contrast, IR is SLC25A28 (and SLC25A37) is already high in proerythroblasts
and remains high throughout erythroblast differentiation. Preliminary data show that an antisense morpholino
directed against a distal intron region can alter IR in the endogenous SLC25A28 gene, indicating the presence
of an intron splicing enhancer that potentially could act via formation of an RNA bridge. The aim of this SHINE
II proposal is to identify cis-regulatory elements in SF3B1 intron 4 and SLC25A28 intron 2 that mediate IR, and
to target key regulatory elements with antisense oligonucleotides in an effort to modulate IR efficiency.
Regulatory elements will be studied in the context of newly constructed minigene splicing reporters already
demonstrated to successfully model IR in transfected cells. Systematic mutation and deletion analysis of the
splicing reporter will reveal which regions impact IR, and guide attempts to block these regions with antisense
reagents in order to modulate IR. These studies are entirely novel since nothing is known about regulation of
IR. The mechanistic information gained here will be relevant to many other genes that also execute IR as part
of their expression repertoire, especially other RNA splicing factors that play a huge role in fine tuning
transcriptome structure. In the future this data may lead to treatment strategies for emerging diseases
characterized by intron retention.
项目摘要/摘要
Share II提案将解决一种新的基因调控机制,即内含子保留(IR),因为它适用于
主要剪接调节因子/血液病基因(SF3B1)和铁稳态基因SLC25A28
(丝裂铁蛋白-2)。这些基因模型代表了发育动态和发育稳定的保留。
事件可能分别受到不同机制的调节。这项提案的目标是定义
机制(S),并获得这种机械性信息可以导致方法的原则证明
以潜在的治疗方式调节保留率。IR成绩单,其定义至少保留了
一个未剪接的内含子,代表了人类许多基因转录输出的丰富部分
红细胞:在SF3B1和SLC25A37(丝裂铁蛋白-1)中高达50%。后者是与
SLC25A28在晚期红细胞中高表达,但SLC25A28更易于研究,因为
内含子大小较小。从理论上讲,IR可以对可翻译的表达施加主要的转录后限制
MRNA在正常发育过程中,并延伸到错误调控可能会影响数量的异常
在推测的‘内含子滞留’疾病中的表达。事实上,异常的内含子保留是骨髓病的一个标志。
ZRSR2突变患者中的发育不良综合征(MDS)。对分子机制知之甚少
控制IR。SF3B1中的IR是发育动态的,随着细胞的成熟,IR的表达从20%上调到50%
从原红细胞(低IR)到嗜正染红细胞(高IR)。一种红外调节模型
该基因涉及内含子中可能与侧翼剪接相互作用的‘诱饵’或‘隐蔽’外显子的活性
阻止内含子切除的站点。相反,在前红细胞中,IR是SLC25A28(和SLC25A37)已经很高
并在整个红细胞分化过程中保持较高水平。初步数据显示,一种反义吗啡
针对远端内含子区域可以改变内源SLC25A28基因的IR,表明存在
可能通过形成RNA桥起作用的内含子剪接增强子。这一闪耀的目的是
II建议确定SF3B1内含子4和SLC25A28内含子2中介导IR的顺式调控元件,以及
用反义寡核苷酸靶向关键调控元件,以调节IR效率。
将在新构建的微型基因剪接记者的背景下研究调控元素
证实成功地在转基因细胞中建立了IR模型。基因的系统突变和缺失分析
剪接记者将揭示哪些区域影响IR,并指导使用反义阻止这些区域的尝试
试剂,以调制IR。这些研究完全是新奇的,因为人们对此一无所知
IR.在这里获得的机械性信息将与许多其他也执行IR的基因相关
它们的表达谱,特别是在微调中发挥巨大作用的其他RNA剪接因子
转录组结构。在未来,这些数据可能会导致新出现的疾病的治疗策略
内含子保留的以内含子保留为特征的
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)
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JOHN G CONBOY其他文献
JOHN G CONBOY的其他文献
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{{ truncateString('JOHN G CONBOY', 18)}}的其他基金
Aberrant RNA processing in MBNL1-deficient mice with erythroid defects
MBNL1 缺陷型红细胞缺陷小鼠的 RNA 加工异常
- 批准号:
9115135 - 财政年份:2014
- 资助金额:
$ 35.07万 - 项目类别:
Aberrant RNA processing in MBNL1-deficient mice with erythroid defects
MBNL1 缺陷型红细胞缺陷小鼠的 RNA 加工异常
- 批准号:
8613315 - 财政年份:2014
- 资助金额:
$ 35.07万 - 项目类别:
Erythroid stage-specific transcriptome expression, dynamics, and regulation
红系阶段特异性转录组表达、动态和调控
- 批准号:
8335204 - 财政年份:2011
- 资助金额:
$ 35.07万 - 项目类别:
Erythroid stage-specific transcriptome expression, dynamics, and regulation
红系阶段特异性转录组表达、动态和调控
- 批准号:
8728222 - 财政年份:2011
- 资助金额:
$ 35.07万 - 项目类别:
Erythroid stage-specific transcriptome expression, dynamics, and regulation
红系阶段特异性转录组表达、动态和调控
- 批准号:
8543725 - 财政年份:2011
- 资助金额:
$ 35.07万 - 项目类别:
Erythroid stage-specific transcriptome expression, dynamics, and regulation
红系阶段特异性转录组表达、动态和调控
- 批准号:
8258173 - 财政年份:2011
- 资助金额:
$ 35.07万 - 项目类别:
Red Cell Band 4.1 - Developmental Changes in RNA Splicing
红细胞带 4.1 - RNA 剪接的发育变化
- 批准号:
7894777 - 财政年份:2009
- 资助金额:
$ 35.07万 - 项目类别:
Red Cell Band 4.1 - Developmental Changes in RNA Splicing
红细胞带 4.1 - RNA 剪接的发育变化
- 批准号:
7533943 - 财政年份:2009
- 资助金额:
$ 35.07万 - 项目类别:
Programmed Changes in Alternative Splicing Within Erythr
Erythr 内选择性剪接的程序化变化
- 批准号:
7087238 - 财政年份:2006
- 资助金额:
$ 35.07万 - 项目类别:
Programmed Changes in Alternative Splicing Within the Erythroid Transcriptome
红细胞转录组内选择性剪接的程序化变化
- 批准号:
7268079 - 财政年份:2006
- 资助金额:
$ 35.07万 - 项目类别:
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