The Thyroid Hormone Nuclear a Receptor: Novel Roles in Erythropoiesis
Sunmi Park, Cho Rong Han and Sheue-yann Cheng*
Gene Regulation Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
Patients with mutations of the thyroid hormone nuclear receptor a (THRA) gene exhibit growth retardation, delayed bone development, and erythroid disorders (e.g., anemia). While the molecular basis underlying growth retardation and delayed bone development have been extensive studied, very little was known on how THRA mutations (TRa1 mutants) caused erythroid disorders. We have previously created a mutant mouse expressing a THRA mutation similar to that identified in patients (denoted as TRa1PV; Thra1PV/+ mice). The Thra1PV/+ mouse faithfully reproduces the retarded growth and delayed bone development as in patients, thus validating that Thra1PV/+ mice could be used to explore how the TRα1PV mutant could act to cause abnormalities in erythropoiesis. We found that Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, β-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. Thus, for the first time, our studies uncovered novel functions of TRa1 in erythropoiesis and provided new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders.
Key Words: Erythropoiesis; thyroid hormone receptor mutations; mouse models; gene regulation; human disease
Sunmi Park, Cho Rong Han and Sheue-yann Cheng*
Gene Regulation Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
Patients with mutations of the thyroid hormone nuclear receptor a (THRA) gene exhibit growth retardation, delayed bone development, and erythroid disorders (e.g., anemia). While the molecular basis underlying growth retardation and delayed bone development have been extensive studied, very little was known on how THRA mutations (TRa1 mutants) caused erythroid disorders. We have previously created a mutant mouse expressing a THRA mutation similar to that identified in patients (denoted as TRa1PV; Thra1PV/+ mice). The Thra1PV/+ mouse faithfully reproduces the retarded growth and delayed bone development as in patients, thus validating that Thra1PV/+ mice could be used to explore how the TRα1PV mutant could act to cause abnormalities in erythropoiesis. We found that Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, β-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. Thus, for the first time, our studies uncovered novel functions of TRa1 in erythropoiesis and provided new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders.
Key Words: Erythropoiesis; thyroid hormone receptor mutations; mouse models; gene regulation; human disease