人类血红蛋白合成是细胞编程的发育阶段特异性调控事件，探索其转换调节机制一直是本领域聚焦的重要科学问题。人zeta珠蛋白基因(HBZ)产物是胚胎期血红蛋白的组成成分，HBZ调控及其与胎儿期alpha珠蛋白基因(HBA)转换的分子机制尚不清楚。通过对中国人alpha地贫携带者大样本队列的研究，我们发现了参与调控HBZ的新基因及顺式元件。本课题应用基因编辑，ATAC/RNA-seq，和3C等技术，通过体外细胞实验和人源化小鼠体内实验，研究这一新基因及其顺式元件在调控HBZ基因及HBZ-HBA转换中的作用机制，研究内容包括: 1. 阐明HBZ和HBA基因发育阶段特异性表达规律；2.鉴定与新基因产物相互作用的调节复合物及工作原理； 3. 构建相关基因调控网络及阐述染色质开放的表观调节机制。研究结果可增加HBZ基因调控及血红蛋白转换的新知识，并可为建立alpha地贫靶向治疗的新路径提供理论基础。

Human hemoglobin synthesis is a programming paradigm of the developmental stage-specific regulation. Exploring the regulatory mechanism of hemoglobin switch has always been an important scientific issue in this field. Human zeta-globin encoded by HBZ gene is a component of embryonic hemoglobin and the molecular mechanism of HBZ gene regulation and of the control of the switch from embryonic to fetal globin expression has largely remained elusive. Based on the study of a large cohort of alpha-thalassemia heterozygotes in southern China, we found a cis-regulatory element and a novel gene coding a protein which binds to it involved in the regulation of human HBZ gene. The present project involving in vitro and in vivo studies intends to uncover the underlying mechanisms of this novel gene in regulating both HBZ gene and the embryonic-to-fetal globin switching by using a group of advanced techniques, such as CRISPR-Cas9 editing, ATAC-seq, RNA-seq and 3C. The main research contents include (1) Clarifying the development stage-specific expression pattern of HBZ and HBA gene. (2) Identifying the regulatory complex interacting with a protein encoded by the novel gene and its working principle. (3) Constructing a related gene regulatory network and uncovering the epigenetic regulatory mechanism responsible for chromatin opening. This study can gain the new knowledge of HBZ gene regulation and hemoglobin switching and provide a theoretical basis for establishment of a new targeted therapeutic approach in alpha-thalassemia.