Abstract
We recently described an erythroid epsilon-globin gene repressor activity, which we named DRED (direct repeat erythroid-definitive). We show that DRED binds with high affinity to DR1 sites in the human embryonic (epsilon-) and fetal (gamma-) globin gene promoters, but the adult beta-globin promoter has no DR1 element. DRED is a 540 kDa complex; sequence determination showed that it contains the nuclear orphan receptors TR2 and TR4. TR2 and TR4 form a heterodimer that binds to the epsilon and gamma promoter DR1 sites. One mutation in a DR1 site causes elevated gamma-globin transcription in human HPFH (hereditary persistence of fetal hemoglobin) syndrome, and we show that this mutation reduces TR2/TR4 binding in vitro. The two receptor mRNAs are expressed at all stages of murine and human erythropoiesis; their forced transgenic expression reduces endogenous embryonic epsilony-globin transcription. These data suggest that TR2/TR4 forms the core of a larger DRED complex that represses embryonic and fetal globin transcription in definitive erythroid cells, and therefore that inhibition of its activity might be an attractive intervention point for treating sickle cell anemia.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adult
-
Anemia, Sickle Cell / metabolism
-
Animals
-
Dimerization
-
Drug Design
-
Erythroid Precursor Cells / metabolism
-
Erythropoiesis
-
Fetal Blood / metabolism
-
Fetal Hemoglobin / biosynthesis
-
Fetal Hemoglobin / genetics
-
Gene Expression Regulation, Developmental*
-
Globins / genetics*
-
Hemoglobinopathies / genetics
-
Humans
-
K562 Cells / metabolism
-
Leukemia, Erythroblastic, Acute / pathology
-
Macromolecular Substances
-
Mice
-
Mice, Transgenic
-
Neoplasm Proteins / metabolism
-
Nerve Tissue Proteins / chemistry
-
Nerve Tissue Proteins / physiology*
-
Nuclear Receptor Subfamily 2, Group C, Member 1
-
Point Mutation
-
Promoter Regions, Genetic / genetics
-
RNA, Messenger / biosynthesis
-
Receptors, Steroid / chemistry
-
Receptors, Steroid / physiology*
-
Receptors, Thyroid Hormone / chemistry
-
Receptors, Thyroid Hormone / physiology*
-
Recombinant Fusion Proteins / physiology
-
Repressor Proteins / chemistry
-
Repressor Proteins / physiology*
-
Transcription, Genetic
-
Tumor Cells, Cultured
Substances
-
Macromolecular Substances
-
NR2C1 protein, human
-
NR2C2 protein, human
-
Neoplasm Proteins
-
Nerve Tissue Proteins
-
Nr2c1 protein, mouse
-
Nr2c2 protein, mouse
-
Nuclear Receptor Subfamily 2, Group C, Member 1
-
RNA, Messenger
-
Receptors, Steroid
-
Receptors, Thyroid Hormone
-
Recombinant Fusion Proteins
-
Repressor Proteins
-
Globins
-
Fetal Hemoglobin