Conditional knockout effects of SMCHD1 in oocytes and embryos

卵母细胞和胚胎中 SMCHD1 的条件性敲除效应

基本信息

  • 批准号:
    10083824
  • 负责人:
  • 金额:
    $ 7.83万
  • 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:
    2020-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

In mammals, the ability to regulate transcription is absent at the start of life. This fundamental ability is acquired during early cleavage stages through the formation of a transcriptionally repressive chromatin state (TRCS), wherein transcriptional enhancers first become necessary. Establishing the TRCS soon after fertilization is vital for two reasons: 1) it is important to suppress activation of endogenous transposable elements, which if activated can be mutagenic, and 2) it is essential to correctly execute the correct transcriptional program for embryo viability. This includes activating and repressing thousands of genes during four successive waves of embryonic genome activation (EGA1 to 4). Failure to establish the TRCS and to regulate EGA waves correctly kills embryos. We discovered that Structural maintenance of chromosomes flexible hinge domain containing protein one (SMCHD1) is a maternal effect gene that potentially orchestrates all of these events. SMCHD1 1) promotes EGA1 termination, 2) is implicated in repressing genes that are up-regulated during EGA2 to 4, and 3) supports inner cell mass (ICM) formation and embryo viability revealing long-term impacts of early SMCHD1 actions. Our overall model is that oocyte-expressed SMCHD1 terminates EGA1 and helps to establish the TRCS to allow correct gene regulation during EGA2. Embryo-expressed SMCHD1 then maintains and extends gene repression and enables optimum control of EGA3 & EGA4 necessary for embryo viability. The study of SMCHD1 mechanisms of action thus provides an important new entry for discovering fundamental mechanisms regulating embryonic genome function and viability. We created a novel floxed Smchd1 allele, which can be used to achieve oocyte-specific ablation of SMCHD1 function, and thus create embryos that lack maternal, embryonic or both sources of SMCHD1, as needed to dissect SMCHD1 earl functions. This proposal will provide essential preliminary data on the phenotype of these knockout animals to allow more in-depth mechanistic studies to be pursued. In Aim 1 we will determine the effects of oocyte-specific knockout on oogenesis and early embryo viability. In Aim 2 we will assess SMCHD1’s role in controlling genes that are activated during the first two waves of gene expression during the 2-cell stage. Overall, this project seeks to solve long-standing fundamental mysteries of how mammalian embryos become competent for life.
在哺乳动物中,调节转录的能力在生命之初是不存在的。这种基本能力是 在早期分裂阶段通过形成转录抑制的染色质状态获得 (TRCS),其中转录增强子首先成为必需的。不久之后建立了TRCS 受精是至关重要的,原因有两个:1)重要的是抑制内源性转座酶的激活, 元素,如果被激活,可能是诱变性的,2)正确执行正确的 胚胎存活率的转录程序。这包括激活和抑制成千上万的基因, 胚胎基因组激活的四个连续波(EGA1至4)。未能建立TRCS, 调节EGA波正确杀死胚胎。 我们发现染色体结构维持的柔性铰链结构域蛋白1 SMCHD1基因是一个母体效应基因,可能协调所有这些事件。SMCHD1 1)促进 EGA1终止,2)涉及在EGA2至4期间上调的阻遏基因,和3) 支持内细胞团(ICM)形成和胚胎活力,揭示早期SMCHD的长期影响1 行动我们的总体模型是,卵母细胞表达的SMCHD1终止EGA1,并有助于建立 TRCS允许EGA 2期间正确的基因调节。然后,胚胎表达的SMCHD1维持并 延长基因抑制,使胚胎生存所需的EGA3和EGA4的最佳控制成为可能。的 因此,SMCHD1作用机制的研究为发现基本的 调节胚胎基因组功能和活力的机制。 我们创造了一个新的floxed Smchd 1等位基因,它可以用来实现卵母细胞特异性消融, SMCHD1功能,从而产生缺乏SMCHD1的母体、胚胎或两者来源的胚胎, 需要剖析SMCHD1的功能。该提案将提供关于以下方面的基本初步数据: 这些基因敲除动物的表型,以允许更深入的机制研究进行追求。在目标1中, 将确定卵母细胞特异性敲除对卵子发生和早期胚胎活力的影响。在目标2中, 评估SMCHD1在控制基因表达的前两波期间被激活的基因中的作用 在2细胞阶段。总的来说,这个项目旨在解决长期存在的基本谜团, 哺乳动物的胚胎开始有生命的能力。

项目成果

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Keith E Latham其他文献

Keith E Latham的其他文献

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{{ truncateString('Keith E Latham', 18)}}的其他基金

Conditional knockout effects of SMCHD1 in oocytes and embryos
卵母细胞和胚胎中 SMCHD1 的条件性敲除效应
  • 批准号:
    10228093
  • 财政年份:
    2020
  • 资助金额:
    $ 7.83万
  • 项目类别:
Epigenetic links from oocyte to postnatal health
卵母细胞与产后健康的表观遗传联系
  • 批准号:
    8626607
  • 财政年份:
    2013
  • 资助金额:
    $ 7.83万
  • 项目类别:
Epigenetic links from oocyte to postnatal health
卵母细胞与产后健康的表观遗传联系
  • 批准号:
    9189638
  • 财政年份:
    2013
  • 资助金额:
    $ 7.83万
  • 项目类别:
Nuclear Reprogramming and Phenotype in Cloned Embryos
克隆胚胎中的核重编程和表型
  • 批准号:
    8712721
  • 财政年份:
    2013
  • 资助金额:
    $ 7.83万
  • 项目类别:
THE PRIMATE EMBRYO GENE EXPRESSION RESOURCE
灵长类胚胎基因表达资源
  • 批准号:
    8357272
  • 财政年份:
    2011
  • 资助金额:
    $ 7.83万
  • 项目类别:
THE PRIMATE EMBRYO GENE EXPRESSION RESOURCE
灵长类胚胎基因表达资源
  • 批准号:
    8172545
  • 财政年份:
    2010
  • 资助金额:
    $ 7.83万
  • 项目类别:
THE PRIMATE EMBRYO GENE EXPRESSION RESOURCE
灵长类胚胎基因表达资源
  • 批准号:
    7959035
  • 财政年份:
    2009
  • 资助金额:
    $ 7.83万
  • 项目类别:
Genetic and Molecular Approach to Identify Ooplasm Reprogramming Factors
鉴定卵质重编程因子的遗传和分子方法
  • 批准号:
    7814932
  • 财政年份:
    2009
  • 资助金额:
    $ 7.83万
  • 项目类别:
Genetic and Molecular Approach to Identify Ooplasm Reprogramming Factors
鉴定卵质重编程因子的遗传和分子方法
  • 批准号:
    7944163
  • 财政年份:
    2009
  • 资助金额:
    $ 7.83万
  • 项目类别:
THE PRIMATE EMBRYO GENE EXPRESSION RESOURCE
灵长类胚胎基因表达资源
  • 批准号:
    7715629
  • 财政年份:
    2008
  • 资助金额:
    $ 7.83万
  • 项目类别:

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