Dietary effects on the sperm epigenome
饮食对精子表观基因组的影响
基本信息
- 批准号:10355482
- 负责人:
- 金额:$ 65.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-14 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnimalsBehaviorBindingBiologicalBiological ProcessBiologyCaenorhabditis elegansCellsChildDNA SequenceDevelopmentDiabetes MellitusDietDissectionEmbryoEmbryo TransferEnvironmentEnvironmental ExposureEpidemiologyEpididymisEpigenetic ProcessExposure toFertilizationFoundationsFutureFuture GenerationsGenerationsGenesGenomeGenomicsGerm CellsGoalsGrantHealthHealth PromotionHeritabilityHumanIndividualInjectionsIntracytoplasmic Sperm InjectionsInvestigationLinkLiteratureMaizeMammalsMeasuresMetabolicMetabolic ControlMetabolic DiseasesMetabolismMicroinjectionsMolecularMolecular BiologyMusOocytesPaternal ExposurePathway interactionsPhenotypePhysiologicalPhysiologyPlayPre-implantation Embryo DevelopmentQuality of lifeRNARNA InterferenceRegulationReproductive BiologyRodentRoleSignal TransductionSmall RNASurveysTimeToxic Environmental SubstancesTransfer RNAblastocystdietaryembryo cultureembryonic stem cellenvironmental disparityepidemiology studyepigenomeepigenomicshuman diseaseinnovationinsightmalenext generationnicotine exposureoffspringpreimplantationpublic health relevancereproductive tractresponsesmall moleculesocial defeatsperm cellsperm functionstem cell modelstressortranscriptome sequencingtransgenerational epigenetic inheritancezygote
项目摘要
Project Summary/Abstract
Although inheritance of DNA sequence underpins the majority of heritability in
biology, it is increasingly clear that information beyond the genome – known as
epigenetic information – is also transmitted to the next generation, with vast
implications for health and development. Over the past decade, we have
developed several paternal-effect paradigms in mice to address how epigenetic
information in gametes affects the phenotype of offspring, and whether an
animal's environmental conditions can affect heritable epigenetic information,
thereby “reprogramming” the offspring's phenotype. We discovered that paternal
environmental exposures can reproducibly alter offspring physiology, and we are
uncovering molecular mechanisms underlying this information transfer, focusing
on the largely unexplored role for sperm RNAs in control of early mammalian
development.
Small RNAs play central roles in well-characterized transgenerational
epigenetic inheritance paradigms such as paramutation in maize and RNA
interference in C. elegans, and it is increasingly clear that small RNAs in
mammalian sperm play key functional roles in the early embryo. Not only is the
overall sperm small RNA payload essential for early development, but the levels
of many specific small RNAs in sperm have been shown to change in response
to paternal environmental conditions. These early and exciting studies motivate a
more thorough characterization of the role of small RNAs in mammalian
development.
Here, we propose to take a three part approach to the regulation and
function of sperm small RNAs in preimplantation embryos. In the first part, we
propose to systematically characterize the functions of sperm RNAs in the early
embryo, manipulating small RNA levels in zygotes and measuring resulting
regulatory consequences by single-embryo RNA-Seq. Next, we plan to survey
the landscape of environmental effects on sperm RNAs, establishing most of the
credible paternal effect paradigms under the same conditions and measuring
sperm RNA levels and resulting early embryonic regulatory consequences in
response to these environmental perturbations. Finally, we seek to uncover the
mechanisms underlying the functions of 5' tRNA fragments, an understudied
class of regulatory molecules which comprise the dominant small RNA species
carried by mature mammalian sperm.
Together, these studies will provide unprecedented insights into the
regulation of small RNA levels in mammalian sperm, and their functions in the
preimplantation embryo. These systematic analyses of epigenetic signals in
sperm will not only reveal new principles of biological inheritance, but will also
enable us to predict and potentially manipulate offspring phenotypes in ways that
promote health.
项目总结/摘要
虽然DNA序列的遗传是遗传的基础,
在生物学中,越来越清楚的是,基因组以外的信息--即
表观遗传信息-也传递给下一代,
对健康和发展的影响。在过去的十年里,我们
在小鼠中开发了几种父系效应范例,以解决表观遗传如何
配子中的信息影响后代的表型,
动物的环境条件可以影响可遗传的表观遗传信息,
从而“重新编程”后代的表型。我们发现父亲
环境暴露可以重复地改变后代的生理学,我们是
揭示这种信息传递的分子机制,
关于精子RNA在控制早期哺乳动物中的作用,
发展
小分子RNA在表征良好的跨代遗传中起着核心作用。
表观遗传的遗传模式,如玉米和RNA的副突变
干扰C.越来越清楚的是,在线虫中的小RNA
哺乳动物精子在早期胚胎中起着关键的功能作用。不仅是
总体精子小RNA有效载荷对早期发育至关重要,但水平
精子中许多特定的小RNA已经被证明会在反应中发生变化,
父亲的环境条件。这些令人兴奋的早期研究激发了
更全面地描述小RNA在哺乳动物中的作用
发展
在这里,我们建议采取三部分的监管方法,
精子小RNA在植入前胚胎中的作用第一部分
建议系统地描述精子RNA在早期发育中的功能,
胚胎,操纵受精卵中的小RNA水平并测量结果
通过单胚胎RNA-Seq的调节后果。接下来,我们计划调查
环境对精子RNA的影响,建立了大部分的
在相同条件和测量条件下,
精子RNA水平和由此产生的早期胚胎调控结果,
对这些环境扰动的反应。最后,我们试图揭示
5' tRNA片段的功能机制,一个未充分研究的
一类调节分子,包括占优势的小RNA种类
由成熟的哺乳动物精子携带
总之,这些研究将提供前所未有的见解,
哺乳动物精子中小RNA水平的调节及其在精子发育中的作用
植入前胚胎这些系统分析的表观遗传信号,
精子不仅将揭示生物遗传的新原理,
使我们能够预测和潜在地操纵后代的表型,
促进健康。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A system for genome-wide histone variant dynamics in ES cells reveals dynamic MacroH2A2 replacement at promoters.
- DOI:10.1371/journal.pgen.1004515
- 发表时间:2014-08
- 期刊:
- 影响因子:4.5
- 作者:Yildirim O;Hung JH;Cedeno RJ;Weng Z;Lengner CJ;Rando OJ
- 通讯作者:Rando OJ
R loops regulate promoter-proximal chromatin architecture and cellular differentiation.
- DOI:10.1038/nsmb.3122
- 发表时间:2015-12
- 期刊:
- 影响因子:16.8
- 作者:Chen PB;Chen HV;Acharya D;Rando OJ;Fazzio TG
- 通讯作者:Fazzio TG
Father-son chats: inheriting stress through sperm RNA.
- DOI:10.1016/j.cmet.2014.05.015
- 发表时间:2014-06-03
- 期刊:
- 影响因子:29
- 作者:Sharma U;Rando OJ
- 通讯作者:Rando OJ
Transcriptome-wide Analysis of Roles for tRNA Modifications in Translational Regulation.
- DOI:10.1016/j.molcel.2017.11.002
- 发表时间:2017-12-07
- 期刊:
- 影响因子:16
- 作者:Chou HJ;Donnard E;Gustafsson HT;Garber M;Rando OJ
- 通讯作者:Rando OJ
Effects of Larval Density on Gene Regulation in Caenorhabditis elegans During Routine L1 Synchronization.
- DOI:10.1534/g3.118.200056
- 发表时间:2018-05-04
- 期刊:
- 影响因子:0
- 作者:Chan IL;Rando OJ;Conine CC
- 通讯作者:Conine CC
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{{ truncateString('OLIVER J RANDO', 18)}}的其他基金
Effects of paternal aging on male reproductive biology and on future generations
父亲衰老对男性生殖生物学和后代的影响
- 批准号:
10272452 - 财政年份:2021
- 资助金额:
$ 65.55万 - 项目类别:
Effects of paternal aging on male reproductive biology and on future generations
父亲衰老对男性生殖生物学和后代的影响
- 批准号:
10624353 - 财政年份:2021
- 资助金额:
$ 65.55万 - 项目类别:
Effects of paternal aging on male reproductive biology and on future generations
父亲衰老对男性生殖生物学和后代的影响
- 批准号:
10461858 - 财政年份:2021
- 资助金额:
$ 65.55万 - 项目类别:
tRNA fragments as transgenerational information carriers
tRNA片段作为跨代信息载体
- 批准号:
8748009 - 财政年份:2014
- 资助金额:
$ 65.55万 - 项目类别:
tRNA fragments as transgenerational information carriers
tRNA片段作为跨代信息载体
- 批准号:
8928182 - 财政年份:2014
- 资助金额:
$ 65.55万 - 项目类别:
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