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Mutations in the Charged Domain of CBX2 Disrupt PRC1 Function In Vivo

机译：CBX2的带电域中的突变体内PRC1功能体内。

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摘要

Epigenetics inheritance is a phenomenon where a cell state is inherited across cellular divisions. It is important for maintaining differentiated cells types, and thus is fundamental to the development of multicellular organisms. Failure in the system can lead to deleterious effects that range from embryonic lethality to the development of diseases such as cancer.;The Polycomb group (PcG) proteins are important regulators of epigenetic inheritance: they maintain the repression of the Hox genes, which specify the body axes of an organism, throughout development and into adulthood. The loss of function of PcG genes therefore leads to homeotic transformations. A mechanistic understanding of PcG function will yield insight into the mechanisms involved in epigenetics inheritance.;The Polycomb Repressive Complex 1 (PRC1) is able to inhibit chromatin remodeling and compact polynucleosomes in vitro ; these activities could represent how stable gene repression is achieved in vivo. However, it has been difficult to determine the biological relevance of these activities because the nature of nucleosomal-level compaction in the nucleus is unknown and there is no direct assay for it.;To circumvent this problem, we adopted an approach where we introduced into mouse embryonic stem cells (mESCs) and mice the mutations that disrupt the in vitro activities. The mutations are specific lysine-to-alanine and arginine-to-alanine substitutions in a positively charged domain of the CBX2 subunit of PRC1. These are known to disrupt PRC1 polynucleosmal compaction activities from previous studies. We compared the mutant mESCs and mice to wild type counterparts for PcG-related phenotypes.;We observed that the mutations prevented the repression of CBX2 (also PRC1) target genes in mESCs. They did not prevent CBX2 from forming PRC1 or binding to chromatin. This suggests that the in vitro activities are specifically involved in inhibiting transcription. Moreover, we observed that the Cbx2 mutant mice exhibit the classic PcG phenotype, which is homeotic transformation in the anterior-posterior axis. The posterior transformations are similar to those observed in the Cbx2-/- mice, indicating that our mutations mimic loss-of-function of Cbx2. Notably, the Cbx2-/- mice had other phenotypes in addition to the PcG phenotype, which we did not observe in our mutants. This indicates that the mutations in the compaction domain of CBX2 specifically disrupted a PcG function during development.;These experimental outcomes are consistent with the hypothesis that the in vitro compaction activity of PRC1 is important for how heritable gene repression can be achieved in vivo.
机译：表观遗传学是一种现象，其中细胞状态跨细胞分裂遗传。这对于维持分化的细胞类型很重要，因此对于多细胞生物的发展至关重要。系统故障可能导致有害影响，范围从胚胎致死到癌症等疾病的发展。Polycomb组（PcG）蛋白是表观遗传遗传的重要调节剂：它们维持Hox基因的阻遏，从而指定了生物体的整个身体轴，直到发育到成年。因此，PcG基因功能的丧失导致同源转化。对PcG功能的机械理解将使我们深入了解表观遗传学遗传所涉及的机制。Polycomb Repressive Complex 1（PRC1）能够在体外抑制染色质重塑和致密多核小体。这些活动可能代表体内如何实现稳定的基因抑制。但是，由于这些核中核小体水平的紧缩的本质是未知的并且没有直接的测定方法，因此很难确定这些活性的生物学相关性。为了避免这个问题，我们采用了一种方法小鼠胚胎干细胞（mESCs）和小鼠的突变会破坏体外活性。突变是PRC1的CBX2亚基带正电荷的结构域中的特定赖氨酸-丙氨酸和精氨酸-丙氨酸取代。从先前的研究中已知这些可破坏PRC1多核小体的紧缩活性。我们将突变的mESC和小鼠与野生型对应的PcG相关表型进行了比较。我们观察到，突变阻止了mESC中CBX2（也为PRC1）靶基因的阻遏。他们没有阻止CBX2形成PRC1或与染色质结合。这表明体外活性特别参与抑制转录。此外，我们观察到Cbx2突变小鼠表现出经典的PcG表型，这是前后轴上的同种异体转化。后转化与在Cbx2-/-小鼠中观察到的相似，表明我们的突变模仿了Cbx2的功能丧失。值得注意的是，除了PcG表型外，Cbx2-/-小鼠还有其他表型，这在我们的突变体中没有观察到。这表明CBX2紧缩结构域中的突变在发育过程中特异性破坏了PcG功能。;这些实验结果与这样的假设一致，即PRC1的体外紧缩活性对于如何在体内实现可遗传基因抑制很重要。

著录项

  • 作者

    Lau, Mei Sheng.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Genetics.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 118 p.
  • 总页数 118
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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