小柯机器人

美国圣裘德儿童研究医院Yong Cheng、Mitchell J. Weiss等研究人员合作解析控制胎儿血红蛋白表达的DNA调控元件。这一研究成果于2021年5月6日在线发表在国际学术期刊《自然—遗传学》上。

研究人员开发了一个高通量框架，可在四个控制红细胞胎儿血红蛋白（HbF）表达的基因位点上绘制具有单核苷酸分辨率的非编码DNA功能，这是一种遗传性决定因素，可改变镰状细胞病（SCD）表型。具体而言，研究人员使用腺嘌呤碱基编辑器ABEmax在307个预测的调控元件中引入了10,156个单独的A•T到G•C转换，并量化了对红细胞HbF表达的影响。

研究人员鉴定了许多调控元件，定义了它们的表观基因组结构，并将其与与SCD队列中HbF表达相关的低频变异体联系起来。靶向SCD供体CD34⁺造血祖细胞中新发现的γ-珠蛋白基因阻遏元件可提高红细胞后代中的HbF水平，从而抑制低氧诱导的镰变。这个发现揭示了以前未知的HbF调控遗传复杂性，并提供了对SCD的潜在治疗方案。

据悉，精确定位功能性非编码DNA序列，并定义其对健康相关性状的贡献是现代遗传学的主要挑战。

附：英文原文

Title: Single-nucleotide-level mapping of DNA regulatory elements that control fetal hemoglobin expression

Author: Li Cheng, Yichao Li, Qian Qi, Peng Xu, Ruopeng Feng, Lance Palmer, Jingjing Chen, Ruiqiong Wu, Tiffany Yee, Jingjing Zhang, Yu Yao, Akshay Sharma, Ross C. Hardison, Mitchell J. Weiss, Yong Cheng

Issue&Volume: 2021-05-06

Abstract: Pinpointing functional noncoding DNA sequences and defining their contributions to health-related traits is a major challenge for modern genetics. We developed a high-throughput framework to map noncoding DNA functions with single-nucleotide resolution in four loci that control erythroid fetal hemoglobin (HbF) expression, a genetically determined trait that modifies sickle cell disease (SCD) phenotypes. Specifically, we used the adenine base editor ABEmax to introduce 10,156 separate AT to GC conversions in 307 predicted regulatory elements and quantified the effects on erythroid HbF expression. We identified numerous regulatory elements, defined their epigenomic structures and linked them to low-frequency variants associated with HbF expression in an SCD cohort. Targeting a newly discovered γ-globin gene repressor element in SCD donor CD34+ hematopoietic progenitors raised HbF levels in the erythroid progeny, inhibiting hypoxia-induced sickling. Our findings reveal previously unappreciated genetic complexities of HbF regulation and provide potentially therapeutic insights into SCD.

DOI: 10.1038/s41588-021-00861-8

Source: https://www.nature.com/articles/s41588-021-00861-8

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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