Structural basis for human ZBTB7A action at the fetal globin promoter
Yang Yang,
Ren Ren,
Lana C. Ly,
John R. Horton,
Fudong Li,
Kate G.R. Quinlan,
Merlin Crossley,
Yunyu Shi,
Xiaodong Cheng
Affiliations
Yang Yang
Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China; Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science and Technology of China, Hefei, China
Ren Ren
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Lana C. Ly
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia
John R. Horton
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Fudong Li
Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science and Technology of China, Hefei, China
Kate G.R. Quinlan
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia
Merlin Crossley
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia; Corresponding author
Yunyu Shi
Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China; Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science and Technology of China, Hefei, China; Corresponding author
Xiaodong Cheng
Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author
Summary: 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.
