Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
基本信息
- 批准号:10160936
- 负责人:
- 金额:$ 85.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAlternative SplicingArchitectureBiologicalCSPG6 geneCell CommunicationCell CycleCell LineageCellsChromatinCommunicationCyclin BDevelopmentDrosophila genusEnsureFailureG2 PhaseGene ExpressionGenesGenetic TranscriptionGerm LinesHomologous GeneImmunoprecipitationLaboratoriesM cellMaintenanceMalignant NeoplasmsMapsMeiosisMessenger RNAMitosisMitoticModelingMolecularProcessProductionProliferatingProphaseProtein IsoformsProteinsRNA-Binding ProteinsRegulationSiteSpermatocytesSpermatogoniaStructureSupporting CellSystemTissuesTranscriptTranslationsadult stem cellcell typein vivomalenovelprecursor cellpreventprogramspromoterrecruitrepairedself-renewaltranscriptome sequencing
项目摘要
Project Summary / Abstract
The switch from proliferation to differentiation is a key regulatory point in the adult stem cell lineages that
underlie tissue maintenance and repair, and failure to cleanly switch may contribute to genesis of cancer. My
laboratory has long used the Drosophila male germ line as a model to investigate how self-renewal,
proliferation and differentiation are regulated in adult stem cell lineages. Several lines of our inquiry have
recently converged on the molecular mechanisms underlying the developmentally programmed transition from
mitotic proliferation to onset of meiosis and differentiation, implicating a number of molecular and cellular
mechanisms in regulating this critical switch. We find that RNA binding proteins involved in translational control
and alternative splicing act cell autonomously to regulate the cessation of proliferation and that progression of
differentiation requires communication from associated somatic support cells. We discovered that a
developmentally regulated alternate choice of site at which certain nascent transcripts are cut to form 3' ends,
leading to production of novel mRNA isoforms with shortened 3'UTRs, controls dramatic changes in the suite
of proteins expressed in differentiating spermatocytes compared to proliferating spermatogonia. We found that
dramatic changes in chromatin open over 2000 new promoters with novel core sequence structure to turn on
the new cell type specific transcription program when cells initiate spermatocyte differentiation. Some of the
earliest genes turned on in this differentiation program encode chromatin associated proteins that prevent
spurious opening of normally cryptic promoters, thus preventing massive misexpression of genes associated
with the wrong cell type. Other transcripts upregulated with differentiation onset encode cell type-specific
translational regulators that delay production of core G2/M cell cycle machinery to program the extended G2
phase of meiotic prophase. Over the next 5 years, we propose to map how these processes collaborate to
form the regulatory circuitry that initiates then executes the switch from proliferation to differentiation. We will
investigate how the RNA binding proteins Bam and Bgcn trigger the switch from mitosis to meiosis by
repressing expression of the alternative splice factor HOW, identify candidate substrates of HOW by
immunoprecipitation followed by RNA-Seq, and assess their function in vivo, including whether they
communicate with adjacent somatic support cells. We will investigate how the switch in proteins expressed
due to alternative 3' end cut site selection on nascent transcripts is regulated and influences differentiation.
We will investigate how the differentiation program is kept off in precursor cells and how cell-type specific
chromatin regulators and proteins that recruit them to target loci set up the new transcription program for
differentiation. To elucidate how the developmental program remodels the cell cycle, we will investigate how
cell-type specific RNA binding proteins first repress, then activate translation of cyclin B during meiotic
prophase and how the DAZ homolog Boule regulates progression into the meiotic divisions.
.
项目摘要/摘要
从增殖到分化的转换是成体干细胞谱系中的一个关键调节点,
组织维护和修复的基础,以及不能干净地切换可能导致癌症的发生。我的
长期以来,实验室一直使用果蝇雄性生殖系作为模型来研究自我更新,
增殖和分化在成体干细胞谱系中受到调节。我们的调查有几条线索
最近集中在发育程序性转变背后的分子机制上
有丝分裂增殖到减数分裂的开始和分化,牵涉到许多分子和细胞
调节这一关键开关的机制。我们发现RNA结合蛋白参与翻译控制
和选择性剪接自主地作用于细胞,调节细胞增殖的停止和进展
分化需要相关的躯体支持细胞进行通讯。我们发现一个
对某些新生转录本被切割成3‘末端的位置进行发育调节的替代选择,
导致产生新的带有缩短的3‘UTRs的信使核糖核酸亚型,控制着序列中的戏剧性变化
在分化的精母细胞和增殖的精原细胞中表达的蛋白质的比例。我们发现
染色质的戏剧性变化开启了2000多个具有新核心序列结构的新启动子
当细胞启动精母细胞分化时,新的细胞类型特定的转录程序。其中一些
在这种分化程序中最早启动的基因编码染色质相关蛋白,从而防止
假性打开通常隐蔽的启动子,从而防止相关基因的大量错误表达
使用错误的细胞类型。其他随着分化开始上调的转录本编码特定的细胞类型
翻译调节子,延迟核心G2/M细胞周期机制的产生,以编程扩展的G2
减数分裂前期。在接下来的5年里,我们建议将这些流程如何协作
形成启动的调节电路,然后执行从增殖到分化的切换。我们会
研究RNA结合蛋白Bam和Bgcn如何通过以下方式触发从有丝分裂到减数分裂的切换
通过抑制选择性剪接因子How的表达,确定How的候选底物
免疫沉淀和RNA-Seq,并评估它们在体内的功能,包括它们是否
与邻近的躯体支持细胞交流。我们将研究蛋白质中的开关是如何表达的
由于选择性3‘末端切割点的选择,新生转录本上的位置选择是受调控的,并影响分化。
我们将研究在前体细胞中如何阻止分化程序,以及细胞类型如何特异性
染色质调节剂和招募它们到靶基因座的蛋白质建立了新的转录程序
差异化。为了阐明发育程序如何重塑细胞周期,我们将研究如何
细胞型特异性RNA结合蛋白在减数分裂过程中首先抑制细胞周期蛋白B的翻译,然后激活细胞周期蛋白B的翻译
以及DAZ同源基因如何调节进入减数分裂的进程。
。
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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MARGARET T FULLER其他文献
MARGARET T FULLER的其他文献
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{{ truncateString('MARGARET T FULLER', 18)}}的其他基金
Genetics and Developmental Biology Training Program
遗传学和发育生物学培训计划
- 批准号:
10630969 - 财政年份:2022
- 资助金额:
$ 85.15万 - 项目类别:
Genetics and Developmental Biology Training Program
遗传学和发育生物学培训计划
- 批准号:
10410329 - 财政年份:2022
- 资助金额:
$ 85.15万 - 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
- 批准号:
10417163 - 财政年份:2020
- 资助金额:
$ 85.15万 - 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
- 批准号:
10630243 - 财政年份:2020
- 资助金额:
$ 85.15万 - 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
- 批准号:
10449061 - 财政年份:2020
- 资助金额:
$ 85.15万 - 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
- 批准号:
10675340 - 财政年份:2020
- 资助金额:
$ 85.15万 - 项目类别:
Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
雄性生殖系成体干细胞谱系增殖和分化的调节
- 批准号:
10200518 - 财政年份:2020
- 资助金额:
$ 85.15万 - 项目类别:
Alternative polydenylation and the regulation of male germ cell differentiation
选择性多聚腺苷酸化和雄性生殖细胞分化的调节
- 批准号:
8822709 - 财政年份:2014
- 资助金额:
$ 85.15万 - 项目类别:
Alternative polydenylation and the regulation of male germ cell differentiation
选择性多聚腺苷酸化和雄性生殖细胞分化的调节
- 批准号:
8936332 - 财政年份:2014
- 资助金额:
$ 85.15万 - 项目类别:
PROJECT 2: TRANSLATIONAL REGULATION OF THE MEIOTIC CELL CYCLE IN THE MALE.
项目 2:男性减数分裂细胞周期的翻译调控。
- 批准号:
8638813 - 财政年份:2014
- 资助金额:
$ 85.15万 - 项目类别:
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