Studies on Silencing

沉默研究

• 批准号: 7965289
• 负责人: AMAR J KLAR
• 金额: $ 32.09万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965289
• 关键词: Anabolism; Binding; Cells; Chromatin; Chromosomes; Coupled; DNA; Deoxyribonucleotides; Development; Epigenetic Process; Fission Yeast; Gene Silencing; Genes; Genetic; Genetic Determinism; Heterochromatin; Inverted Repeat Sequences; Maintenance; Malignant Neoplasms; Mating Types; Meiosis; Mitosis; Molecular Biology; Mutation; Nature; Protein Family; Proteins; RNA Interference; Research; System; Work; Yeasts; cancer type; cell growth; developmental genetics; dosage; imprint; interest; protein complex

<B>Research</b>:<BR><BR>The Developmental Genetics Section is mainly interested in the genetics and molecular biology of gene silencing and mating-type switching in <I>Schizosaccharomyces pombe</i>. In this yeast, the mating-type region consists of three loci called <I>mat1</i>, <I>mat2</i>, and <I>mat3</i>. The <I>mat2</i> and <I>mat3</i> loci are always silent and only act as donors of genetic information required for switching the transcriptionally active <I>mat1</i> locus.<BR><BR><B>Studies on Silencing</b><BR><BR>We previously found that silencing mechanism involves a chromosomally heritable epigenetic alteration, presumably of chromatin associated with the <I>mat</i> region. In fission yeast, an epigenetic imprint marking the mating-type (<I>mat2/3</i>) region contributes to inheritance of the silenced state, but the nature of the imprint is not known. We show that a chromodomain-containing swi6 protein is a dosage-critical component involved in imprinting the <I>mat</i> locus. The establishment and maintenance of the imprint are tightly coupled to the recruitment and the persistence of swi6 at the <I>mat2/3</i> region during mitosis as well as meiosis. Remarkably, swi6p remains bound to the <I>mat2/3</i> interval throughout the cell and itself seems to be a component of the imprint. Our analyses suggest that the unit of inheritance at the <I>mat2/3</i> locus comprises the DNA plus the associated swi6 protein complex. Interestingly the silenced domain is bracketed by 1.2KB inverted repeat sequences that block spreading of heterochromatin to adjoining regions of chromosome. We have discovered that mutations in deoxyribonucleotide biosynthesis cause spreading of silencing across these heterochromatin barriers. The spreading of heterochromatin across barriers required functional Atf1/Pcr1, ATF-CREB family proteins, but not the RNA-interference Dcr1, Ago1, or Rdp1 factors, previously implicated in silencing. Our work on will continues to define the genetic determinants of silencing. This work has direct implication for explaining eucaryotic cellular differentiation and for cancer development as disruption of epigenetic controls constitutes a prominant mechanism of unwanted cellular growth.

<B研究/B：BR BR 发育遗传学组主要研究 裂殖酵母中的基因沉默和交配型转换 庞贝岛在这种酵母中，交配型区域由三个位点组成 称为I mat 1/i， <I mat 2/i，并且 <I mat3/i.的 <I mat 2/i和 <I mat 3/i loci总是沉默的，只作为 转换转录活性基因所需的遗传信息的供体 <I材料1/i> locus.& lt;BR BR B研究 沉默/B BR BR我们 先前发现沉默机制涉及染色体遗传的表观遗传， 改变，可能是与染色体相关的染色质改变， <I mat/i region.在裂变酵母中， 标记匹配类型的印记（I mat 2/3/i） 区域有助于沉默状态的继承，但印记的性质不是 知道的我们发现，含有染色体结构域的swi 6蛋白是剂量关键组分 参与了I mat/i基因座的印记。的 印记的建立和维持与征聘和 swi 6在I mat 2/3/i区域的持久性 在有丝分裂和减数分裂期间。值得注意的是，swi 6p仍然与 <I mat 2/3/i间隔贯穿整个单元， 它本身似乎是印记的一部分。我们的分析表明， 在Imat 2/3/i基因座处的遗传包括 DNA加上相关的swi 6蛋白复合物。有趣的是，沉默域是 由1.2KB反向重复序列包围，该序列阻断异染色质的扩散， 染色体的相邻区域。我们发现脱氧核糖核苷酸的突变 生物合成导致沉默跨越这些异染色质屏障扩散。扩频 异染色质跨越屏障需要功能性Atf 1/Pcr 1，ATF-CREB家族蛋白， 但不包括先前参与沉默的RNA干扰Dcr 1、Ago 1或Rdp 1因子。 我们的工作将继续定义沉默的遗传决定因素。这项工作 解释真核细胞分化和癌症的直接意义 发育作为表观遗传控制的破坏构成了不想要的发育的抑制机制。 细胞生长