Epigenetic regulation of active chromatin’

活性染色质的表观遗传调控

• 批准号: 452337045
• 负责人: Professor Dr. Peter Burkhard Becker
• 金额: --
• 依托单位: Lehrstuhl Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/452337045?language=en
• 关键词: Epigenetic; regulation; active; chromatin

The compensation for X chromosome monosomy in Drosophila serves as an instructive example for epigenetic regulation of active chromatin. Dosage compensation in flies adjusts the transcription of the single X chromosome in males by roughly 2-fold activation to match the combined output of the two female X’s. Central to this regulation is the Dosage Compensation Complex (DCC), which consists of 5 male-specific-lethal protein subunits and non-coding roX RNA.According to the prevalent model, the exclusive activation of genes on the X chromosome involves genetic and epigenetic principles. First, the DCC selectively binds to some 300 DNA sequence-defined ‘High Affinity Sites’ (HAS) on the X. From there it ‘reaches out’ to epigenetically marked target genes to boost their transcription through histone acetylation. This proposal addresses unsolved questions about the nature of the epigenetic chromatin modification and the ‘reader’ and ‘writer’ functions of the DCC that allows it to selectively acetylate active chromatin. The current model states that DCC bound to a HAS searches the chromosomal neighborhood for transcribed chromatin, using the chromodomain of the MSL3 subunit as a ‘reader head’. This domain can bind nucleosomes marked by methylation of histone H3 at lysine 36 (H3K36me3), a modification that is placed co-transcriptionally. MSL3 is connected to the acetyltransferase MOF through the scaffold protein MSL1. Accordingly, the MSL3-nucleosome interaction recruits MOF to active chromatin, where it acetylates H4K16. This acetylation is thought to facilitate transcription through chromatin unfolding. We wish to critically evaluate this model and explore the principles that allow regional H4K16 acetylation in the chromosome. Our biochemical approach is aimed at deciphering molecular mechanism.Reinforcing feedback loops are better known for the maintenance of repressive chromatin structures, such as constitutive and facultative heterochromatin. Our study addresses an unusual case, where features of active chromatin trigger additional activation. The epigenetic reader in the DCC (a methyllysine binder) and the writer enzyme (a histone acetyltransferase) exemplify widely used, evolutionary conserved regulatory molecules. Knowledge gained from our study will have wide implications beyond the specific case of sex chromosome regulation in flies.

果蝇X染色体单体性的补偿是活性染色质表观遗传调控的一个有指导意义的例子。果蝇中的剂量补偿通过大约2倍的激活来调整雄性中单个X染色体的转录，以匹配两个雌性X的组合输出。 剂量补偿复合物（DCC）是这种调控的核心，它由5个雄性特异性致死蛋白亚基和非编码roX RNA组成。根据流行的模型，X染色体上基因的排他性激活涉及遗传和表观遗传原理。首先，DCC选择性地结合到X染色体上大约300个DNA序列定义的“高亲和力位点”（HAS）。从那里它“伸出”到表观遗传标记的靶基因，通过组蛋白乙酰化促进它们的转录。该提案解决了关于表观遗传染色质修饰的性质以及DCC的“阅读器”和“写入器”功能（允许其选择性乙酰化活性染色质）的未解决的问题。目前的模型指出，DCC结合到一个HAS搜索转录的染色质的染色体附近，使用的染色体结构域的MSL 3亚基作为一个'读取头'。该结构域可以结合由组蛋白H3在赖氨酸36（H3 K36 me 3）处的甲基化标记的核小体，这是一种共转录放置的修饰。MSL 3通过支架蛋白MSL 1与乙酰转移酶MOF连接。因此，MSL 3-核小体相互作用将MOF募集到活性染色质，在那里它使H4 K16乙酰化。这种乙酰化被认为通过染色质展开促进转录。我们希望批判性地评估这一模型，并探索原则，允许区域H4 K16乙酰化的染色体。我们的生物化学方法旨在破译分子机制。加强反馈环更好地为抑制性染色质结构的维持所知，例如组成性和兼性异染色质。我们的研究解决了一个不寻常的情况下，活性染色质的功能触发额外的激活。DCC中的表观遗传阅读器（一种甲基赖氨酸结合剂）和书写酶（一种组蛋白乙酰转移酶）是广泛使用的进化保守调节分子。从我们的研究中获得的知识将具有广泛的意义，超出了果蝇性染色体调控的具体情况。