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Mutant Thyroid Gene Linked to Aberrant Histone Modifications

Mutation associated with resistance to thyroid hormone

THURSDAY, March 26 (HealthDay News) -- A mutation in the thyroid hormone receptor associated with resistance to thyroid hormone is associated with aberrant histone modifications that increase expression of thyrotropin-releasing hormone (TRH), according to a study published online March 19 in Endocrinology.

Ryohei Umezawa and colleagues from Gunma University Graduate School of Medicine in Maebashi, Japan, investigated the regulation of the TRH gene in the presence of a previously described thyroid hormone receptor mutant (F455S) using pituitary-derived cells expressing the normal or mutant receptor. The mutant receptor had been previously described as being found in an 11-year-old girl with pituitary resistance to thyroid hormone and was associated with abnormal histone deacetylation.

The researchers found that in the presence of the normal thyroid hormone receptor, lysines 9 and 14 of histone H3 were acetylated and then transiently deacetylated after treatment with thyroid hormone. Lysine 4 of H3 was methylated in the presence of the normal thyroid hormone receptor and the methylation level was reduced after long-term treatment with 3,5,3'-triiodothyronine (T3). T3 treatment also led to reduced levels of thyroid hormone receptor and phosphorylated RNA polymerase II. In the presence of the mutant receptor, methylation of lysine 4 was unaffected, while lysines 9 and 14 were hyperacetylated and T3-induced deacetylation decreased, the report indicates.

"These findings demonstrated that 1) negative regulation of the TRH gene by thyroid hormone involves both the acetylation and methylation of specific residues of histone tails, and changing the amount of thyroid hormone receptor, and 2) the major impairment to histone modifications in F455S was hyperacetylation of the specific histone tails," Umezawa and colleagues conclude.

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