使用 HBB 基因敲除人类红系祖细胞模型对 β-地中海贫血进行多组学分析,International Journal of Molecular Sciences

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使用 HBB 基因敲除人类红系祖细胞模型对 β-地中海贫血进行多组学分析
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2022-03-07 , DOI: 10.3390/ijms23052807
Guoqiang Zhou ₁ , Haokun Zhang ₁ , Anning Lin ₁ , Zhen Wu ₁ , Ting Li ₂ , Xumin Zhang ₁ , Hongyan Chen ₁ , Daru Lu _{1,

3}

Affiliation

β-地中海贫血是一种可能与显着发病率和死亡率相关的血液疾病。HBG1/2表达增加可改善β-地中海贫血的严重程度。与未受影响的人群相比，一些 β-地中海贫血患者的红细胞中 HBG1/2 表达水平升高。然而，上调的幅度并未达到自我修复的阈值，因此，在 HBB 缺乏的情况下，HBG1/2 表达的分子机制需要进一步阐明。在这里，我们进行了一项多组学研究，检查 HUDEP2 细胞系 (HBB-KO) 的 HBB 纯合敲除中的染色质可及性、转录组、蛋白质组和磷酸化模式。我们发现 HBB-KO 细胞中 HBG1/2 的上调不是由 H3K4me3 介导的遗传补偿反应诱导的。人红系祖细胞中 HBB 的缺失导致 ROS 水平增加和氧化应激的产生，从而导致细胞凋亡率增加。此外，为了响应氧化应激，观察到较慢的细胞周期进程和增殖。此外，启动应激红细胞生成导致细胞内 HBG1/2 表达增加。该分子模型还在来自 β-血红蛋白病患者的造血干细胞的单细胞转录组中得到验证。这些发现进一步加深了对 HBG1/2 基因调控网络的理解，并为β-地中海贫血表型多样性提供了新的临床见解。作为对氧化应激的反应，观察到较慢的细胞周期进程和增殖。此外，启动应激红细胞生成导致细胞内 HBG1/2 表达增加。该分子模型还在来自 β-血红蛋白病患者的造血干细胞的单细胞转录组中得到验证。这些发现进一步加深了对 HBG1/2 基因调控网络的理解，并为β-地中海贫血表型多样性提供了新的临床见解。作为对氧化应激的反应，观察到较慢的细胞周期进程和增殖。此外，启动应激红细胞生成导致细胞内 HBG1/2 表达增加。该分子模型还在来自 β-血红蛋白病患者的造血干细胞的单细胞转录组中得到验证。这些发现进一步加深了对 HBG1/2 基因调控网络的理解，并为β-地中海贫血表型多样性提供了新的临床见解。

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Multi-Omics Analysis in β-Thalassemia Using an HBB Gene-Knockout Human Erythroid Progenitor Cell Model

β-thalassemia is a hematologic disease that may be associated with significant morbidity and mortality. Increased expression of HBG1/2 can ameliorate the severity of β-thalassemia. Compared to the unaffected population, some β-thalassemia patients display elevated HBG1/2 expression levels in their red blood cells. However, the magnitude of up-regulation does not reach the threshold of self-healing, and thus, the molecular mechanism underlying HBG1/2 expression in the context of HBB-deficiency requires further elucidation. Here, we performed a multi-omics study examining chromatin accessibility, transcriptome, proteome, and phosphorylation patterns in the HBB homozygous knockout of the HUDEP2 cell line (HBB-KO). We found that up-regulation of HBG1/2 in HBB-KO cells was not induced by the H3K4me3-mediated genetic compensation response. Deletion of HBB in human erythroid progenitor cells resulted in increased ROS levels and production of oxidative stress, which led to an increased rate of apoptosis. Furthermore, in response to oxidative stress, slower cell cycle progression and proliferation were observed. In addition, stress erythropoiesis was initiated leading to increased intracellular HBG1/2 expression. This molecular model was also validated in the single-cell transcriptome of hematopoietic stem cells from β-hemoglobinopathy patients. These findings further the understanding of HBG1/2 gene regulatory networks and provide novel clinical insights into β-thalassemia phenotypic diversity.

更新日期：2022-03-07

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