Regulation Of Cellular Proliferation And Diversity In Dr

博士中细胞增殖和多样性的调节

• 批准号: 6671860
• 负责人: JAMES A. KENNISON
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 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/6671860
• 关键词: Drosophilidae; arthropod genetics; cell differentiation; cell growth regulation; cell proliferation; chromosome aberrations; developmental genetics; gene induction /repression; gene interaction; genetic models; genetic transcription; homeobox genes; molecular cloning; nucleic acid sequence; transcription factor

The goal of the Section on Drosophila Gene Regulation is to understand the regulation of homeotic gene function in Drosophila. The homeotic genes specify segmental identities in Drosophila at both the embryonic and adult stages. They encode homeodomain-containing transcription factors that control cell fates by regulating the transcription of downstream target genes. The homeotic genes are expressed in precise spatial patterns that are crucial for the proper determination of segmental identities. Both loss of expression and ectopic expression in the wrong tissues lead to changes in segmental identities. These changes in identity provide a powerful assay to identify the trans-acting factors that regulate the homeotic genes and the cis-acting sequences through which they act. Both the homeotic genes and the trans-acting factors that regulate them are conserved between Drosophila and man. In addition to many conserved developmental genes, at least half of the disease and cancer-causing genes in man are conserved in Drosophila, making Drosophila a very important model system for the study of human development and disease. Genetic studies have identified the trithorax group of genes that are required for expression or function of the homeotic genes. Reduced function of the trithorax group genes mimics loss of function of the homeotic genes. Many trithorax group proteins are subunits of chromatin-remodeling or transcriptional coactivator complexes. The brahma, moira, and osa genes encode subunits of the Brahma chromatin-remodeling complex, which is conserved from yeast to human. To further understand the function of the Brahma complex, we have been characterizing mutations that interact with mutations in the Brahma complex. As part of these studies, we have recently isolated and characterized mutations in the Asf1 histone chaperone in collaboration with F. Karch (University of Geneva), J. Tamkun (University of California, Santa Cruz), and P. Verrijzer (Leiden University). We have shown that Asf1 is important for the structure of heterochromatin and that it interacts both functionally and physically with the Brahma chromatin-remodeling complex. In collaboration with J. Eissenberg and A. Shilatifard (St. Louis University) and A. Christensen (University of Nebraska), we have also isolated and characterized mutations in Su(Tpl), which encodes the Drosophila homolog of the ELL RNA polymerase II transcriptional elongation factor. We have shown that Su(Tpl) is required for the transcription of multiple developmental genes, including the Sex combs reduced homeotic gene. Su(Tpl) is within the first intron of the Mi-2 gene, which is required for transcriptional repression of the homeotic genes. In collaboration with W. McGinnis (University of California, San Diego), we have also isolated and characterized mutations in the Deaf-1 gene. The DEAF-1 protein was originally identified as a factor that bound to a cis-regulatory enhancer element from the Deformed homeotic gene. We have shown that Deaf-1 is essential for embryonic development.

有关果蝇基因调节的部分的目的是了解果蝇中同源基因功能的调节。同源基因在胚胎和成人阶段指定果蝇中的分段身份。它们编码含同源域的转录因子，通过调节下游靶基因的转录来控制细胞命运。同源基因以精确的空间模式表达，这对于适当确定分段身份至关重要。错误组织中表达的丧失和异位表达都会导致分段身份的变化。这些身份的变化提供了一种强大的测定法，以识别调节同源基因的跨作用因素和通过其作用的顺式作用序列。果蝇和人之间的同源基因和调节它们的跨作用因子都保守。除了许多保守的发育基因外，果蝇中至少有一半的疾病和引起癌症的基因是保守的，这使果蝇成为研究人类发育和疾病的非常重要的模型系统。 遗传研究已经鉴定出了同源基因表达或功能所必需的三丝体基因。 Trithorax组基因的功能降低模仿了同源基因功能的丧失。许多Trithorax组蛋白是染色质复制或转录共激活因子复合物的亚基。梵天，Moira和OSA基因编码梵天染色质复合物的亚基，该复合物是从酵母到人的保守的。为了进一步了解梵天复合物的功能，我们一直在表征与梵天复合物中突变相互作用的突变。作为这些研究的一部分，我们最近与F. Karch（日内瓦大学），J。Tamkun（加利福尼亚大学，圣克鲁斯大学）和P. Verrijzer（莱顿大学）合作，在ASF1组蛋白伴侣伴侣中孤立并表征了突变。我们已经表明，ASF1对于异染色质的结构很重要，并且它与梵天染色质复合复合物在功能和物理上相互作用。与J. Eissenberg和A. Shilatifard（圣路易斯大学）和A. Christensen（内布拉斯加州大学）合作，我们还隔离了SU（TPL）中的突变，该突变（TPL）编码了Ell RNA Polymerase II转录延长因子的果蝇同源物。我们已经表明，SU（TPL）是转录多个发育基因的转录所必需的，包括性梳子减少了同源基因。 SU（TPL）是MI-2基因的第一个内含子，这是对同源基因的转录抑制所必需的。与W. McGinnis（加利福尼亚大学圣地亚哥分校）合作，我们还孤立了聋哑1基因的突变。聋-1蛋白最初被鉴定为与变形同源基因的顺式调节增强子元件结合的因素。我们已经表明，聋哑1对于胚胎发育至关重要。