小柯机器人

美国费城儿童医院Gerd A. Blobel小组发现，双重功能NFI因子控制胎儿血红蛋白在成人红细胞中的沉默。相关论文于2022年5月26日在线发表于国际学术期刊《自然—遗传学》。

研究人员通过CRISPR-Cas9基因筛选，确定了NFI转录因子家族的两个成员（NFIA和NFIX）作为HBG1/2的抑制因子。与胎儿细胞相比，NFIA和NFIX在成年红细胞中的表达水平较高，并且在培养细胞和人鼠异种移植中协同抑制HBG1/2。基因组分析、基因组编辑和DNA结合试验表明，NFIA和NFIX的强大协同活性部分是由于它们能够刺激BCL11A（一种已知的HBG1/2基因的沉默因子）的表达，部分是由于直接压制HBG1/2基因。因此，NFI因子是胎儿到成人的β-球蛋白生产转换过程中的多功能调节因子。

据悉，胎儿型β-球蛋白样基因HBG1和HBG2在成年红细胞前体细胞中被沉默的机制仍然是人类生物学中的一个基本问题，并对镰状细胞病和β-地中海贫血症具有治疗意义。

附：英文原文

Title: Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells

Author: Qin, Kunhua, Huang, Peng, Feng, Ruopeng, Keller, Cheryl A., Peslak, Scott A., Khandros, Eugene, Saari, Megan S., Lan, Xianjiang, Mayuranathan, Thiyagaraj, Doerfler, Phillip A., Abdulmalik, Osheiza, Giardine, Belinda, Chou, Stella T., Shi, Junwei, Hardison, Ross C., Weiss, Mitchell J., Blobel, Gerd A.

Issue&Volume: 2022-05-26

Abstract: The mechanisms by which the fetal-type β-globin-like genes HBG1 and HBG2 are silenced in adult erythroid precursor cells remain a fundamental question in human biology and have therapeutic relevance to sickle cell disease and β-thalassemia. Here, we identify via a CRISPR–Cas9 genetic screen two members of the NFI transcription factor family—NFIA and NFIX—as HBG1/2 repressors. NFIA and NFIX are expressed at elevated levels in adult erythroid cells compared with fetal cells, and function cooperatively to repress HBG1/2 in cultured cells and in human-to-mouse xenotransplants. Genomic profiling, genome editing and DNA binding assays demonstrate that the potent concerted activity of NFIA and NFIX is explained in part by their ability to stimulate the expression of BCL11A, a known silencer of the HBG1/2 genes, and in part by directly repressing the HBG1/2 genes. Thus, NFI factors emerge as versatile regulators of the fetal-to-adult switch in β-globin production.

DOI: 10.1038/s41588-022-01076-1

Source: https://www.nature.com/articles/s41588-022-01076-1

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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