Genome-wide analysis of pseudogenes reveals HBBP1's human-specific essentiality in erythropoiesis and implication in β-thalassemia
Genome-wide analysis of pseudogenes reveals HBBP1's human-specific essentiality in erythropoiesis and implication in β-thalassemia
复制标题
假基因的全基因组分析揭示了 HBBP1 在红细胞生成中的人类特异性重要性及其对 b 地中海贫血的影响
DOI：
10.1016/j.devcel.2020.12.019
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发表时间：
2021-02-22
影响因子：
11.8
通讯作者：
Yu, Jia
中科院分区：
文献类型：
--
作者：
Ma, Yanni;Liu, Siqi;Yu, Jia
人类基因组包含14，000个重复或逆转录的假基因。鉴于它们作为调控RNA的功能和低保守性，我们假设假基因可以塑造人类特异性表型。为了验证这一点，我们进行了共表达分析，发现假基因表现出组织特异性表达，特别是在骨髓中。通过整合遗传数据，我们确定了一个骨髓特异性重复假基因HBBP 1（eta-珠蛋白），它与β-地中海贫血有关。广泛的功能测定表明，HBBP 1通过结合RNA结合蛋白（RBP）HNRNPA 1上调TAL 1（红细胞生成的关键调节因子）对红细胞生成至关重要。HBBP 1/TAL 1相互作用导致β地中海贫血患者的症状较轻。比较研究进一步表明，HBBP 1/TAL 1相互作用是人类特异性的。全基因组分析表明，重复的假基因通常与RBP结合，而与逆转录酶基因相比，与microRNA结合的情况较少。总之，我们不仅证明了假基因可以驱动人类进化，而且还提供了关于其功能景观的见解。
The human genome harbors 14,000 duplicated or retroposed pseudogenes. Given their functionality as regulatory RNAs and low conservation, we hypothesized that pseudogenes could shape human-specific phenotypes. To test this, we performed co-expression analyses and found that pseudogene exhibited tissue-specific expression, especially in the bone marrow. By incorporating genetic data, we identified a bone-marrow-specific duplicated pseudogene, HBBP1 (eta-globin), which has been implicated in beta-thalassemia. Extensive functional assays demonstrated that HBBP1 is essential for erythropoiesis by binding the RNA-binding protein (RBP), HNRNPA1, to upregulate TAL1, a key regulator of erythropoiesis. The HBBP1/TAL1 interaction contributes to a milder symptom in beta-thalassemia patients. Comparative studies further indicated that the HBBP1/TAL1 interaction is human-specific. Genome-wide analyses showed that duplicated pseudogenes are often bound by RBPs and less commonly bound by microRNAs compared with retropseudogenes. Taken together, we not only demonstrate that pseudogenes can drive human evolution but also provide insights on their functional landscapes.