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NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor ?1.

ABSTRACT: Thyroid hormone receptor ? (THRA) gene mutations, via dominant negative mode, cause erythroid abnormalities in patients. Using mice expressing a dominant negative TR?1 mutant (TR?1PV; Thra1 PV/+ mice), we showed that TR?1PV acted directly to suppress the expression of key erythroid genes, causing erythroid defects. The nuclear receptor corepressor 1 (NCOR1) was reported to mediate the dominant negative effects of mutated TR?1. However, how NCOR1 could regulate TR?1 mutants in erythroid defects in vivo is not known. In the present study, we crossed Thra1 PV/+ mice with mice expressing a mutant Ncor1 allele (NCOR1?ID; Ncor1 ?ID mice). TR?1PV mutant cannot bind to NCOR1?ID. The expression of NCOR1?ID ameliorated abnormalities in the peripheral blood indices, and corrected the defective differentiation potential of progenitors in the erythroid lineage. The defective terminal erythropoiesis of lineage-negative bone marrow cells of Thra1 PV/+ mice was rescued by the expression of NCOR1?ID. De-repression of key erythroid genes in Thra1 PV/+ Ncor1 ?ID/?ID mice led to partial rescue of terminal erythroid differentiation. These results indicate that the inability of TR?1PV to recruit NCOR1?ID to form a repressor complex relieved the deleterious actions of TR?1 mutants in vivo. NCOR1 is a critical novel regulator underpining the pathogenesis of erythroid abnormalities caused by TR?1 mutants.

SUBMITTER: Han CR

PROVIDER: S-EPMC5741760 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor α1.

Han Cho Rong CR Park Sunmi S Cheng Sheue-Yann SY

Scientific reports 20171222 1

Thyroid hormone receptor α (THRA) gene mutations, via dominant negative mode, cause erythroid abnormalities in patients. Using mice expressing a dominant negative TRα1 mutant (TRα1PV; Thra1 <sup>PV/+</sup> mice), we showed that TRα1PV acted directly to suppress the expression of key erythroid genes, causing erythroid defects. The nuclear receptor corepressor 1 (NCOR1) was reported to mediate the dominant negative effects of mutated TRα1. However, how NCOR1 could regulate TRα1 mutants in erythroi ...[more]

PMID: 29273766

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Project description:Background: Mutations of thyroid hormone receptor α1 (TRα1) cause resistance to thyroid hormone (RTHα). Patients exhibit growth retardation, delayed bone development, anemia, and bradycardia. By using mouse models of RTHα, much has been learned about the molecular actions of TRα1 mutants that underlie these abnormalities in adults. Using zebrafish models of RTHα that we have recently created, we aimed to understand how TRα1 mutants affect the heart function during this period. Methods: In contrast to human and mice, the thra gene is duplicated, thraa and thrab, in zebrafish. Using CRISPR/Cas9-mediated targeted mutagenesis, we created C-terminal mutations in each of two duplicated thra genes in zebrafish (thraa 8-bp insertion or thrab 1-bp insertion mutations). We recently showed that these mutant fish faithfully recapitulated growth retardation as found in patients and thra mutant mice. In the present study, we used histological analysis, gene expression profiles, confocal fluorescence, and transmission electron microscopy (TEM) to comprehensively analyze the phenotypic characteristics of mutant fish heart during development. Results: We found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and the decreased circulating blood speed and reduced expression of contractile genes indicated weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days postfertilization (juveniles). Furthermore, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by TEM, suggesting that the abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish. Conclusions: Using a zebrafish model of RTHα, the present study demonstrated for the first time that TRα1 mutants could act to cause abnormal heart structure, weaken contractility, and disrupt sarcomere organization that affect heart functions. These findings provide new insights into the bradycardia found in RTHα patients.

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NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor ?1.

Publications

NCOR1 modulates erythroid disorders caused by mutations of thyroid hormone receptor α1.

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