Imperial College London
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ProfessorGrahamWilliams

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Clinical Professor of Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 1383graham.williams

 
 
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Location

 

10N5Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Freudenthal:2019:10.1089/thy.2018.0399,
author = {Freudenthal, B and Shetty, S and Butterfield, NC and Logan, JG and Han, CR and Zhu, X-G and Astapova, I and Hollenberg, AN and Cheng, S-Y and Bassett, JHD and Williams, G},
doi = {10.1089/thy.2018.0399},
journal = {Thyroid},
title = {Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha},
url = {http://dx.doi.org/10.1089/thy.2018.0399},
volume = {29},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background Thyroid hormones act in bone and cartilage via thyroid hormone receptor α (TRα). In the absence of T3, TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone α (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation and bone dysplasia. Treatment with thyroxine has been of limited benefit even in mildly affected individuals and there is a need for new therapeutic strategies. We hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. Methods We determined the skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα, (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα, and (iii) Thra1PV/+Ncor1ΔID/ΔID double mutant adult mice. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results Thra1PV/+ mice had a severe skeletal dysplasia characterized by short stature, abnormal bone morphology and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization and strength. Thra1PV/+Ncor1ΔID/ΔID double mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bo
AU  - Freudenthal,B
AU  - Shetty,S
AU  - Butterfield,NC
AU  - Logan,JG
AU  - Han,CR
AU  - Zhu,X-G
AU  - Astapova,I
AU  - Hollenberg,AN
AU  - Cheng,S-Y
AU  - Bassett,JHD
AU  - Williams,G
DO  - 10.1089/thy.2018.0399
PY  - 2019///
SN  - 1050-7256
TI  - Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha
T2  - Thyroid
UR  - http://dx.doi.org/10.1089/thy.2018.0399
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30760120
UR  - http://hdl.handle.net/10044/1/67910
VL  - 29
ER  -
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