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.
项目总结/摘要
这个SHINE II提案将解决基因调控的新机制,内含子保留(IR),因为它适用于
一个主要剪接调节因子/血液病基因(SF 3B 1)和一个铁稳态基因SLC 25 A28
(mitoferrin-2)。这些基因模型代表发育动态和发育稳定的保留
这些事件可能分别由不同的机制调节。本提案的目标是定义
机制,并获得该机制信息可以导致用于
以潜在的治疗方式调节保留。IR成绩单,根据定义,至少保留
一个未剪接的内含子,代表了人类许多基因转录产物的丰富部分
成红细胞:SF 3B 1和SLC 25 A37(线粒体铁蛋白-1)中高达50%。后者是一个密切的paradise
SLC 25 A28在晚期成红细胞中高度表达,但SLC 25 A28更适合研究,因为
较小的内含子大小。理论上,IR可以对可翻译基因的表达施加主要的转录后限制。
mRNA在正常发育过程中,并通过扩展错误调节可以影响定量异常,
在假定的“内含子保留”疾病中的表达。事实上,异常的内含子保留是骨髓-
在具有ZRSR 2突变的患者中的发育不良综合征(MDS)。对分子机制知之甚少
SF 3B 1中的IR是发育动态的,随着细胞成熟从20%上调至50
从原成红细胞(较低IR)到嗜正染性成红细胞(较高IR)。IR调节的一种模型
在这个基因中,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
阻止内含子切除的位点。相比之下,IR是SLC 25 A28(和SLC 25 A37)在原成红细胞中已经很高
并且在成红细胞分化过程中保持高水平。初步数据显示,
针对远端内含子区域的基因可以改变内源性SLC 25 A28基因中的IR,表明存在
内含子剪接增强子,可能通过形成RNA桥发挥作用。本次闪耀的目的
II建议鉴定SF 3B 1内含子4和SLC 25 A28内含子2中介导IR的顺式调节元件,
用反义寡核苷酸靶向关键调控元件以调节IR效率。
调控元件将在新构建的小基因剪接报告的背景下进行研究,
证明在转染细胞中成功模拟IR。系统性突变和缺失分析
剪接报告基因将揭示哪些区域影响IR,并指导尝试用反义核酸阻断这些区域。
这些研究是完全新颖的,因为对IR的调节一无所知。
红外光谱这里获得的机制信息将与许多其他基因相关,这些基因也作为IR的一部分执行IR。
特别是其他RNA剪接因子,它们在基因的微调中发挥着巨大的作用,
转录组结构在未来,这些数据可能会导致新兴疾病的治疗策略
以内含子保留为特征。
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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