@article{7b15b22ec45d472ca35c1f6f1d8456f4,
title = "Single-nucleotide-level mapping of DNA regulatory elements that control fetal hemoglobin expression",
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 A•T to G•C 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.",
author = "Li Cheng and Yichao Li and Qian Qi and Peng Xu and Ruopeng Feng and Lance Palmer and Jingjing Chen and Ruiqiong Wu and Tiffany Yee and Jingjing Zhang and Yu Yao and Akshay Sharma and Hardison, {Ross C.} and Weiss, {Mitchell J.} and Yong Cheng",
note = "Funding Information: R. Kurita and Y. Nakamura (Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan) provided the HUDEP-2 cells. X. An (Laboratory of Membrane Biology, New York Blood Center) provided the anti-Band 3 antibody. We thank the St. Jude Children{\textquoteright}s Research Hospital Flow Cytometry core facility for performing the cell sorting, the Hartwell Center core facility for performing the high-throughput sequencing and the Center for Advanced Genome Engineering for performing the targeted deep sequencing. We thank K. A. Laycock for scientific editing of the manuscript. This work was supported by St. Jude Children{\textquoteright}s Research Hospital and ALSAC, National Institutes of Health grants R35GM133614 (to Y.C.), P01HL053749 (to M.J.W.) and R24DK106766 (to M.J.W., R.C.H. and Y.C.), the St. Jude Collaborative Research Consortium (to M.J.W. and Y.C.) and Doris Duke Foundation grant 2017093 (M.J.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jun,
doi = "10.1038/s41588-021-00861-8",
language = "English (US)",
volume = "53",
pages = "869--880",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "6",
}