Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation,Nature Genetics

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Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation
Nature Genetics ( IF 31.7 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41588-019-0568-7
Anindita Basak _{1,

2,

3} , Mathias Munschauer ₃ , Caleb A Lareau _{1,

2,

3,

4} , Kara E Montbleau _{1,

2,

3,

5} , Jacob C Ulirsch _{1,

2,

3,

4} , Christina R Hartigan ₃ , Monica Schenone ₃ , John Lian _{6,

7} , Yaomei Wang ₈ , Yumin Huang _{8,

9} , Xianfang Wu ₁₀ , Lee Gehrke _{6,

7} , Charles M Rice ₁₀ , Xiuli An _{8,

11} , Helen A Christou ₁₂ , Narla Mohandas ₈ , Steven A Carr ₃ , Jane-Jane Chen _{6,

7} , Stuart H Orkin _{1,

2,

3} , Eric S Lander _{3,

13,

14} , Vijay G Sankaran _{1,

2,

3}

Affiliation

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
Boston University School of Medicine, Boston, MA, USA.
Institute for Biomedical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA.
New York Blood Center, New York, NY, USA.
The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
School of Life Science, Zhengzhou University, Zhengzhou, China.
Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.

Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and β-thalassemia¹. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development^2,3,4,5,6,7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of messenger RNA (mRNA) translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating let-7 microRNAs, and that BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities.

中文翻译：

LIN28B介导的BCL11A翻译调控对人血红蛋白转换的控制

增加胎儿血红蛋白 (HbF) 的产生可以改善镰状细胞病和 β-地中海贫血¹的严重程度。BCL11A 抑制编码 HbF 的基因，并通过其在发育过程中的表达变化来调节人类血红蛋白的转换^2,3,4,5,6,7。然而，BCL11A 发育表达的机制仍然是神秘的。在这里，我们显示 BCL11A 在人类造血发育过程中的信使 RNA (mRNA) 翻译水平受到调节。尽管在发育早期 BCL11A 蛋白质合成减少，但 BCL11AmRNA 继续与核糖体相关联。通过公正的基因组和蛋白质组学分析，我们证明了以与 BCL11A 相反的模式发育表达的 RNA 结合蛋白 LIN28B 直接与核糖体和BCL11A mRNA 相互作用。此外，我们表明LIN28B 通过直接相互作用抑制BCL11A mRNA 翻译，这与它在调节 let-7 microRNA 中的作用无关，并且 BCL11A 是 LIN28B 介导的 HbF 诱导的主要目标。我们的研究结果揭示了人类血红蛋白转换的一种以前未被认识的机制，它为新的治疗机会提供了启示。

更新日期：2020-01-20

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