Novel imprint control regions (ICRs) responsive to environmental exposures
响应环境暴露的新型印记控制区域(ICR)
基本信息
- 批准号:10655605
- 负责人:
- 金额:$ 59.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-10 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:5 year oldAdolescentAffectAgeAlanine TransaminaseAllelesBioinformaticsBiological AssayBirthBlood PressureBody mass indexBody measure procedureCadmiumCellsCentral obesityChildChildhoodChromatin StructureChronic DiseaseCommunitiesConsensusCpG dinucleotideCuesCustomCytosineDNADNA MethylationDataDepositionDesire for foodDevelopmentDiseaseEarly DiagnosisEctodermElementsEmbryoEmbryonic DevelopmentEndodermEnvironmental ExposureEnvironmental PollutantsEpidemiologyEpigenetic ProcessExposure toFatty acid glycerol estersFunctional disorderGRB10 geneGene DosageGene ExpressionGenesGeneticGenomeGenomic ImprintingGerm CellsGerm LayersGoalsGrowthGrowth DisordersH19 geneHealthHeavy MetalsHumanHuman GenomeHyperglycemiaHyperlipidemiaHypertensionIGF2 geneIndividualKnowledgeLifeLife Cycle StagesLinkLipidsLiver DysfunctionMapsMeasurementMeasuresMediatingMesodermMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolismMethodsMethylationModificationMolecular ProfilingNucleic Acid Regulatory SequencesNutrientObesityOutcomePLAGL1 geneParentsPathway interactionsPeripheralPlacentaPrevalenceProtocols documentationProxyRecordsReportingRoleSamplingSatiationScreening procedureSiteSomatic CellSpecific qualifier valueSpecimenTestingTissuesTrace metalTriglyceridesagedbisulfite sequencingcell typeclinically actionablecohortcomorbiditydeep sequencingenvironmental chemicalepigenomefetalgenetic variantgenome-widehistone modificationhuman tissueimprintinterestnon-alcoholic fatty liver diseasenovelobesity riskoffspringprehypertensionprenatalprenatal exposurepreservationresponsetoxic metalwhole genome
项目摘要
PROJECT SUMMARY/ABSTRACT
The increased prevalence of obesity in the US and elsewhere has led to the hypothesis that epigenetic mechanisms mediate
associations between environmental cues and obesity outcomes. However, epigenetic regions that alter obesity risk are still
largely unknown, and the current lack of a screening tool for comprehensive measurement of epigenetic modifications
hampers the identification of associated regions. Such a screen that could also be applied to any disease or exposure of
interest would be of great utility for a broad range of human health studies. The interpretation of human epigenetic data
generated using genome-scale approaches is hampered by several obstacles. Firstly, the available data are largely based
on methylation differences measured in DNA obtained cross-sectionally at different ages throughout the life course, yet DNA
methylation marks are known to vary by age. Secondly, methylation measurements are made in accessible peripheral cell
types accessible from otherwise healthy individuals, and variability of epigenetic marks between cell types means that
measurements from these cells do not always correlate with those from cell types that contribute to diseases. Finally,
alteration to epigenetic marks can be caused by disease, and this temporal ambiguity between exposure and outcome
complicates causal inference. To overcome these obstacles, we have comprehensively identified DNA methylation-
controlled regulatory regions for genomically imprinted genes, mapping the first draft of the human “imprint-ome”.
Epigenetically regulated imprinted genes are estimated to comprise 1-2% (200-400 genes) of the human genome and are
critical in the development of the early embryo; however, only ~24 imprint control regions (ICRs), regulating 70 to 80 genes,
are presently defined. Monoallelic expression of imprinted genes is regulated by parent-of-origin specific DNA methylation at
ICRs that are established prior to germ-layer specification and maintained in somatic tissues throughout life. Our overarching
goal is to leverage the newly identified ICRs, to develop a custom platform for measuring them in human specimens, and
statistically identify the subset of the human imprint-ome associated with one of the most common trace metals—cadmium,
a heavy metal that is sequestered by the placenta, contributing to placental dysfunction. Cadmium related methylation will
also be examined in relation to children’s metabolic outcomes. Once developed, this ICR custom platform will be invaluable
in identifying regions of developmental epigenetic perturbation associated with other early-acquired diseases or exposures,
creating new opportunities for early detection and understanding the fetal origins of human health and disease.
项目概要/摘要
美国和其他地区肥胖患病率的增加引发了这样的假说:表观遗传机制介导
环境因素与肥胖结果之间的关联。然而,改变肥胖风险的表观遗传区域仍然存在
很大程度上未知,目前缺乏全面测量表观遗传修饰的筛选工具
妨碍了相关区域的识别。这样的屏幕也可以应用于任何疾病或接触
兴趣对于广泛的人类健康研究将具有很大的实用性。人类表观遗传数据的解释
使用基因组规模方法产生的结果受到几个障碍的阻碍。首先,现有数据主要基于
在整个生命过程中不同年龄的横截面中测量 DNA 的甲基化差异,但 DNA
已知甲基化标记随年龄而变化。其次,在可接近的外周细胞中进行甲基化测量
可从其他健康个体获得的类型,以及细胞类型之间表观遗传标记的变异性意味着
这些细胞的测量结果并不总是与导致疾病的细胞类型的测量结果相关。最后,
表观遗传标记的改变可能是由疾病引起的,并且暴露和结果之间的这种时间模糊性
使因果推理复杂化。为了克服这些障碍,我们全面鉴定了DNA甲基化-
基因组印记基因的受控调控区域,绘制了人类“印记组”的初稿。
据估计,表观遗传调控的印记基因占人类基因组的 1-2%(200-400 个基因),
对早期胚胎的发育至关重要;然而,只有约 24 个印记控制区 (ICR),调节 70 至 80 个基因,
目前已定义。印记基因的单等位基因表达受亲本特异性 DNA 甲基化的调节
ICR 在胚层规范之前建立并在整个生命过程中维持在体细胞组织中。我们的首要任务
目标是利用新发现的 ICR,开发一个定制平台来测量人体样本中的 ICR,以及
统计上确定了与最常见的痕量金属之一镉相关的人类印记组的子集,
一种被胎盘隔离的重金属,导致胎盘功能障碍。镉相关甲基化将
还应检查与儿童代谢结果的关系。一旦开发完成,这个 ICR 定制平台将具有无价的价值
在识别与其他早期获得性疾病或暴露相关的发育表观遗传扰动区域时,
为早期检测和了解人类健康和疾病的胎儿起源创造新的机会。
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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Cathrine Hoyo其他文献
Cathrine Hoyo的其他文献
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{{ truncateString('Cathrine Hoyo', 18)}}的其他基金
Prenatal stress and diet, and the fetal epigenome
产前压力和饮食,以及胎儿表观基因组
- 批准号:
10523353 - 财政年份:2022
- 资助金额:
$ 59.81万 - 项目类别:
Prenatal stress and diet, and the fetal epigenome
产前压力和饮食,以及胎儿表观基因组
- 批准号:
10665054 - 财政年份:2022
- 资助金额:
$ 59.81万 - 项目类别:
Novel imprint control regions (ICRs) responsive to environmental exposures
响应环境暴露的新型印记控制区域(ICR)
- 批准号:
10296917 - 财政年份:2021
- 资助金额:
$ 59.81万 - 项目类别:
Characterizing the Human Imprint Regulatory Regions Associated with Childhood Obesity
表征与儿童肥胖相关的人类印记调节区域
- 批准号:
10442527 - 财政年份:2019
- 资助金额:
$ 59.81万 - 项目类别:
Characterizing the Human Imprint Regulatory Regions Associated with Childhood Obesity
表征与儿童肥胖相关的人类印记调节区域
- 批准号:
10180994 - 财政年份:2019
- 资助金额:
$ 59.81万 - 项目类别:
Characterizing the Human Imprint Regulatory Regions Associated with Childhood Obesity
表征与儿童肥胖相关的人类印记调节区域
- 批准号:
10011940 - 财政年份:2019
- 资助金额:
$ 59.81万 - 项目类别:
Characterizing the Human Imprint Regulatory Regions Associated with Childhood Obesity
表征与儿童肥胖相关的人类印记调节区域
- 批准号:
10662238 - 财政年份:2019
- 资助金额:
$ 59.81万 - 项目类别:
Follow-up and Maintenance of the Newborn Epigenetics STudy (NEST) Cohort
新生儿表观遗传学研究 (NEST) 队列的随访和维护
- 批准号:
10443683 - 财政年份:2018
- 资助金额:
$ 59.81万 - 项目类别:
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