美国圣裘德儿童研究医院Mitchell J. Weiss课题组揭示低氧诱导因子1α对γ-球蛋白表达的激活作用。相关论文于2022年10月12日在线发表在《自然》杂志上。
据研究人员介绍，在出生前后，人类红细胞（RBC）中的球蛋白表达从γ-球蛋白转向β-球蛋白，这导致胎儿血红蛋白（HbF，α2γ2）逐渐被成人血红蛋白（HbA，α2β2）取代。这一过程促使人们开发出创新的方法，通过提高产后红细胞中的HbF水平来治疗镰状细胞病和β地中海贫血。研究人员通过CRISPR-Cas9筛选出调节HbF表达的泛素-蛋白酶体成分，提供了对球蛋白基因转换的治疗性见解。在红细胞前体中，von Hippel-Lindau（VHL）E3泛素连接酶的耗竭稳定了其泛素化靶标，即缺氧诱导因子1α（HIF1α），从而诱导γ-球蛋白基因转录。
从机制上讲，HIF1α-HIF1β异构体与BGLT3中的认知DNA元件结合，BGLT3是一个长的非编码RNA基因，位于串联的γ-球蛋白基因HBG1和HBG2的下游2.7kb。随后，转录激活剂被招募，染色质被打开，γ-球蛋白基因和其上游增强子之间的长距离相互作用增加。在缺氧或抑制脯氨酰羟化酶结构域酶的情况下，HbF也会发生类似的诱导，这些酶以HIF1α为靶标，由VHL E3泛素连接酶进行泛素化。
这些研究结果将球蛋白基因调控与典型的缺氧适应联系起来，提供了压力红细胞生成过程中HbF的诱导机制，并提出了一种治疗β-血红蛋白病的新方法。
附：英文原文
Title: Activation of γ-globin expression by hypoxia-inducible factor 1α
Author: Feng, Ruopeng, Mayuranathan, Thiyagaraj, Huang, Peng, Doerfler, Phillip A., Li, Yichao, Yao, Yu, Zhang, Jingjing, Palmer, Lance E., Mayberry, Kalin, Christakopoulos, Georgios E., Xu, Peng, Li, Chunliang, Cheng, Yong, Blobel, Gerd A., Simon, M. Celeste, Weiss, Mitchell J.
Issue&Volume: 2022-10-12
Abstract: Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to β-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2β2)1. This process has motivated the development of innovative approaches to treat sickle cell disease and β-thalassaemia by increasing HbF levels in postnatal RBCs2. Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR–Cas9 screen for ubiquitin–proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor1α (HIF1α)3,4, to induce γ-globin gene transcription. Mechanistically, HIF1α–HIF1β heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7kb downstream of the tandem γ-globin genes HBG1 and HBG2. This was followed by the recruitment of transcriptional activators, chromatin opening and increased long-range interactions between the γ-globin genes and their upstream enhancer. Similar induction of HbF occurred with hypoxia or with inhibition of prolyl hydroxylase domain enzymes that target HIF1α for ubiquitination by the VHL E3 ubiquitin ligase. Our findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during stress erythropoiesis and suggest a new therapeutic approach for β-haemoglobinopathies.
DOI: 10.1038/s41586-022-05312-w
Source: https://www.nature.com/articles/s41586-022-05312-w