RUI: Defining histone variant regulatory mechanisms for sperm-specific gene expression

生育能力取决于正常形成的精子、卵母细胞和胚胎。形成每一种独特细胞类型的一个关键因素是在发育过程中对不同组基因的调节。然而，细胞如何协调受精前后控制细胞命运的一系列基因的表达仍然是个谜。在这个项目中，研究人员的研究使用线虫，一种模式蠕虫生物，专注于被称为组蛋白H2A变体的基因表达的关键调控因素。该项目的目标是确定特定的过氧化氢变异体用来调节精子和胚胎发育所需的不同基因集的专门机制。这项工作将在旧金山州立大学进行，这是一所服务于城市少数群体的公立机构，主要是本科生。研究人员将让不同的学生直接参与研究，应用分子、计算和细胞学方法来确定H2A变异的基因调控机制。学生们将在传统期刊或“微出版物：生物学”上发表他们的研究，这是一个直接向公众提供快速同行评议的高质量研究结果的新平台。这些研究将促进STEM领域不同学生的职业发展。研究人员将确定线虫精子特异性组蛋白H2A变异体HTAS-1在三个目标中的作用。在目标1中，学生将使用RNA-seq来定义hTAS-1如何在精子形成过程中调节目标位置的转录。在目标2中，学生将从公共数据库和合作者中挖掘数据，以确定hTAS-1与组蛋白修饰、转录因子、组织特异性转录本和决定精子命运或调节基因表达的顺式元件的重叠。在缺乏HTAS-1的情况下，转录谱的差异将支持HTAS-1在转录起始、延伸和与其他系统中的H2A变体相关的共转录加工机制中的功能。在目标3中，他们将跟踪受精前后依赖于hTAS-1的单个基因表达的动态，以确定hTAS-1的表观遗传学作用。这些方法将共同定义协同调节器、顺式调节元件以及在精子分化和胚胎发育过程中用来调节基因表达的机制。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Fertility depends on properly formed sperm, oocytes, and embryos. A critical factor to form each unique cell type is the regulation of distinct sets of genes during development. However, how cells coordinate the expression of sets of genes that control cell fate before and after fertilization is still mysterious. In this project, the investigator's studies use C. elegans, a model worm organism, to focus on key regulators of gene expression called histone H2A variants. The goal of this project is to define the specialized mechanisms used by a specific H2A variant to regulate distinct sets of genes required for sperm and embryo development. This work will be conducted at San Francisco State University, an urban minority-serving public institution with a mostly undergraduate student population. The investigators will engage the diverse students directly in the research to apply molecular, computational, and cytological methods to determine H2A variant gene regulation mechanisms. Students will publish their research in traditional journals or "micropublication: biology", a new platform to provide rapid peer-reviewed, high-quality findings directly to the public. These studies will advance the career development of diverse students in STEM fields. The investigators will determine roles of the C. elegans sperm-specific histone H2A variant HTAS-1 in three aims. In Aim 1, students will use RNA-seq to define how HTAS-1 regulates transcription of target sites during sperm formation. In Aim 2, students will mine data from public databases and collaborators to define overlap of HTAS-1 with histone modifications, transcription factors, tissue-specific transcripts, and cis elements that specify sperm fate or regulate gene expression. Differences in transcriptomic profiles in the absence of HTAS-1 will support HTAS-1 function in mechanisms of transcriptional initiation, elongation, and co-transcriptional processing linked to H2A variants in other systems. In Aim 3, they will follow the dynamics of HTAS-1-dependent expression of individual genes before and after fertilization to determine epigenetic roles of HTAS-1. Together, these approaches will define co-regulators, cis regulatory elements, and mechanisms that H2A variants use to regulate gene expression during sperm differentiation and embryo development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.