Analysis of gene regulation in the vertebrate beta-globin loci has been instructive in establishing many of the founding principles used in differential tissue- and developmental stage-specific transcriptional control. I propose to continue analysis of the trans-acting factors that are employed in differentially regulating the human beta-globin genes, in particular to address the basic mechanisms underlying erythroid tissue- and stage- specific gene regulation (hemoglobin switching). During the previous award period, we discovered and then purified a novel repressor complex (DRED) that suppresses murine embryonic globin gene transcription in adult erythroid cells. The DNA binding scaffold for DRED is composed of a heterodimer formed between two orphan nuclear receptors, TR2 and TR4. Given the clear and immediate potential for therapeutic development for treating hemoglobinopathies, and in particular sickle cell anemia, this discovery should be fully explored. Experiments are proposed here to determine whether the murine and human orthologs of DRED regulate the embryonic and fetal beta-type globin genes in genetic and biochemical experiments to be conducted in loss- and gain-of-function mouse models as well as in primary (CD34+) fetal and adult human erythroid progenitor cells and human embryonic stem cells (HSF-6, WA01 and BG01). We will also determine the identity of other co-repressor constituents of the DRED complex using in vivo biotin affinity labeling followed by tandem mass spectrometry; these co- effectors can also be developed as therapeutic targets for inactivation that may lead to adult erythroid gamma- (or epsilon-) globin gene induction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Erythrocyte and Leukocyte Biology Study Section (ELB)
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Evans, Gregory
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University of Michigan Ann Arbor
Anatomy/Cell Biology
Schools of Medicine
Ann Arbor
United States
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Cui, Shuaiying; Tanabe, Osamu; Sierant, Michael et al. (2015) Compound loss of function of nuclear receptors Tr2 and Tr4 leads to induction of murine embryonic ?-type globin genes. Blood 125:1477-87
Cui, Shuaiying; Lim, Kim-Chew; Shi, Lihong et al. (2015) The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice. Blood 126:386-96
Shi, Lihong; Sierant, M C; Gurdziel, Katherine et al. (2014) Biased, non-equivalent gene-proximal and -distal binding motifs of orphan nuclear receptor TR4 in primary human erythroid cells. PLoS Genet 10:e1004339
Shi, Lihong; Lin, Yu-Hsuan; Sierant, M C et al. (2014) Developmental transcriptome analysis of human erythropoiesis. Hum Mol Genet 23:4528-42
Cui, Shuaiying; Tanabe, Osamu; Lim, Kim-Chew et al. (2014) PGC-1 coactivator activity is required for murine erythropoiesis. Mol Cell Biol 34:1956-65
Hosoya, Tomonori; Clifford, Mary; Losson, RĂ©gine et al. (2013) TRIM28 is essential for erythroblast differentiation in the mouse. Blood 122:3798-807
Suzuki, Mikiko; Yamazaki, Hiromi; Mukai, Harumi Y et al. (2013) Disruption of the Hbs1l-Myb locus causes hereditary persistence of fetal hemoglobin in a mouse model. Mol Cell Biol 33:1687-95
Shi, Lihong; Cui, Shuaiying; Engel, James D et al. (2013) Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med 19:291-4
Campbell, Andrew D; Cui, Shuaiying; Shi, Lihong et al. (2011) Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proc Natl Acad Sci U S A 108:18808-13
Cui, Shuaiying; Kolodziej, Katarzyna E; Obara, Naoshi et al. (2011) Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic ?-type globin promoters in differentiated adult erythroid cells. Mol Cell Biol 31:3298-311

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