Structural basis for human ZBTB7A action at the fetal globin promoter

Yang, Yang; Ren, Ren; Ly, Lana C.; Horton, John R.; Li, Fudong; Quinlan, Kate G.R.; Crossley, Merlin; Shi, Yunyu; Cheng, Xiaodong

doi:10.1016/j.celrep.2021.109759

Structural basis for human ZBTB7A action at the fetal globin promoter

Journal Article · Wed Sep 29 00:00:00 EDT 2021 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2021.109759· OSTI ID:1824691

Yang, Yang ^[1]; Ren, Ren ^[2]; ^[3]; Horton, John R. ^[2]; Li, Fudong ^[4]; ^[3]; ^[3]; Shi, Yunyu ^[1]; ^[2]

Univ. of Science and Technology of China, Hefei (China). Hefei National Lab. for Physical Sciences at Microscale. School of Life Sciences. Division of Life Sciences and Medicine. Ministry of Education Key Lab. for Membraneless Organelles and Cellular Dynamics
Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States). Dept. of Epigenetics and Molecular Carcinogenesis
Univ. of New South Wales, Sydney, NSW (Australia). School of Biotechnology and Biomolecular Sciences
Univ. of Science and Technology of China, Hefei (China). Ministry of Education Key Lab. for Membraneless Organelles and Cellular Dynamics

Elevated levels of fetal globin protect against β-hemoglobinopathies, such as sickle cell disease and β-thalassemia. Two zinc-finger (ZF) repressors, BCL11A and ZBTB7A/LRF, bind directly to the fetal globin promoter elements positioned at -115 and -200, respectively. Here, we describe X-ray structures of the ZBTB7A DNA-binding domain, consisting of four adjacent ZFs, in complex with the -200 sequence element, which contains two copies of four consecutive C:G base pairs. ZF1 and ZF2 recognize the 5' C:G quadruple, and ZF4 contacts the 3' C:G quadruple. Natural non-coding DNA mutations associated with hereditary persistence of fetal hemoglobin (HPFH) impair ZBTB7A DNA binding, with the most severe disruptions resulting from mutations in the base pairs recognized by ZF1 and ZF2. Our results firmly establish ZBTB7A/LRF as a key molecular regulator of fetal globin expression and inform genome-editing strategies that inhibit repressor binding and boost fetal globin expression to treat hemoglobinopathies.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1824691

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 13 Vol. 36; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
BCL11A
C2H2 zinc-finger transcription factors
ZBTB7A
fetal form of β-globin
globin gene activation
globin switching
leukemia/lymphoma-related factor
γ-globin

Structural basis for human ZBTB7A action at the fetal globin promoter

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