Genome-wide analysis of pseudogenes reveals HBBP1's human-specific essentiality in erythropoiesis and implication in β-thalassemia.

Abstract

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 (η-globin), which has been implicated in β-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 β-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.

• Authors: Yanni Ma, Siqi Liu, Jie Gao, Chunyan Chen, Xin Zhang, Hao Yuan, Zhongyang Chen, Xiaolin Yin, Chenguang Sun, Yanan Mao, Fanqi Zhou, Yi Shao, Qian Liu, Jiayue Xu, Li Cheng, Daqi Yu, Pingping Li, Ping Yi, Jiahuan He, Guangfeng Geng, Qing Guo, Yanmin Si, Hualu Zhao, Haipeng Li, Graham L Banes, He Liu, Yukio Nakamura, Ryo Kurita, Yue Huang, Xiaoshuang Wang, Fang Wang, Gang Fang, James Douglas Engel, Lihong Shi, Yong E Zhang, Jia Yu
• Journal: Developmental cell (Dev Cell) Vol. 56 Issue 4 Pg. 478-493.e11 (02 22 2021) ISSN: 1878-1551 [Electronic] United States
• PMID: 33476555 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Heterogeneous Nuclear Ribonucleoprotein A1
• RNA, Long Noncoding
• RNA, Messenger
• T-Cell Acute Lymphocytic Leukemia Protein 1
• hnRNPA1 protein, human
• TAL1 protein, human
• Globins

Topics

• Binding, Competitive
• Bone Marrow (metabolism)
• Cell Differentiation (genetics)
• Cell Line
• Erythroid Cells (metabolism, pathology)
• Erythropoiesis (genetics)
• Globins (genetics)
• Heterogeneous Nuclear Ribonucleoprotein A1 (metabolism)
• Humans
• Organ Specificity (genetics)
• Protein Binding
• Protein Stability
• Pseudogenes
• RNA Stability
• RNA, Long Noncoding (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Species Specificity
• T-Cell Acute Lymphocytic Leukemia Protein 1 (genetics, metabolism)
• beta-Thalassemia (genetics)