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Regulation of Gene Expression by Thyroid Hormones: Relation to Growth and Development

Gregory A. Brent

10.1002/cphy.cp070524

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Thyroid Hormone Response Elements
1.1 Standard Configuration and Sequences
1.2 Complex and Unusual Response Elements
1.3 Single Half‐Site Elements
1.4 Influence of Response Element Position and Orientation on Gene Regulation
1.5 Elements that Confer a Negative Response to Thyroid Hormone
1.6 Response Elements that Confer Thyroid Hormone Receptor Isoform Specificity
2 Thyroid Hormone Regulation of Growth Hormone and Growth Factor Gene Expression
2.1 Characterization of DNA Elements that Confer Thyroid Hormone Response
2.2 Species Differences in Growth Hormone Gene Regulation
2.3 Influence of Retinoic Acid and cAMP on Thyroid Hormone Regulation of Gene Expression
2.4 Interactions of Thyroid Hormone Receptor and Pit‐1 in Regulation of Growth Hormone Gene Expression
2.5 Thyroid Hormone Stimulation of Growth Hormone–Releasing Hormone Receptor Gene Expression
2.6 Thyroid Hormone Regulation of Growth Factors
3 Regulation of Gene Expression in Nervous System Development
3.1 Expression of Thyroid Hormone Receptor Isoforms in Neural Development
3.2 Effects of Hypothyroidism on Neural Development
3.3 Regulation of Neural Gene Expression
4 Regulation of Gene Expression in Bone
4.1 Clinical Effects of Thyroid Hormone on Bone
4.2 In Vitro Effects of Thyroid Hormone on Bone Cells
5 Thyroid Hormone Metabolism: Regulation of Ligand Availability
5.1 Characteristics and Tissue Distribution of Deiodinases
5.2 Regulation of Deiodinase Expression
5.3 Developmental Regulation of Deiodinase Expression
6 Thyroid Hormone Regulation of Gene Expression in Amphibian Metamorphosis
6.1 Regulation of Thyroid Hormone Receptor Gene Expression
6.2 Prolactin–Thyroid Hormone Interactions and Effects on Gene Expression
7 Growth and Developmental Abnormalities as A Consequence of Thyroid Hormone Deficiency
7.1 Congenital Hypothyroidism
7.2 Hypothyroidism of Infancy and Childhood
7.3 Iodine and Selenium Deficiency
7.4 Endemic Cretinism
8 Influence of Mutant Thyroid Receptors on Growth and Development
8.1 Genetic Basis of Resistance to Thyroid Hormone
8.2 Influence of Response Element Configuration and Thyroid Hormone Receptor Isoform on Response Inhibition by Mutant Receptors
8.3 Growth in Resistance to Thyroid Hormone as a Function of the Thyroid Hormone Receptor Mutant and Thyroid Hormone Treatment
8.4 Pituitary Resistance to Thyroid Hormone, Clinical Manifestations, and Mechanism
8.5 Animal Models of Resistance to Thyroid Hormone
9 Summary
Figure 1. Figure 1.

The thyroid hormone receptor (TR) complexes that bind to specific DNA sequences, the thyroid hormone response elements (TREs), located upstream of the transcription start site (shown by arrow), are shown. These complexes confer positive and negative gene regulation. The TR can bind as a homodimer, monomer, or a heterodimer with the 9‐cis retinoic acid (9‐cis RA) receptor (RXR). The various combinations are shown for products of the TRα and TRβ genes, as well as of the RXR α, β and γ genes. All of these complexes have been demonstrated in vitro, but there are likely to be preferential in vivo interactions. The preferential binding site configurations are shown for homodimers (inverted palindrome with a 6 bp gap), monomer (single half‐site), and TR/RXR heterodimer (direct repeat with 4 bp gap). These TRE arrangements are detailed in Figure 2.
Figure 2. Figure 2.

The three major patterns of 6 bp half‐site sequences for thyroid hormone response elements (TREs) are shown, including a direct repeat with a 4 bp gap, an inverted palindrome with a 6 bp gap, and a palindrome. Wild‐type elements show some variation in sequence and in spacing relative to the idealized element. The influence of spacing on the direct repeat element is shown for the retinoic acid receptor (RAR), thyroid hormone receptor (TR), vitamin D receptor (VDR), 9‐cis retinoic acid receptor (RXR), and the peroxisome proliferator–activated receptor (PPAR). Palindromic elements are shown for the estrogen response element (ERE) and the glucocorticoid response elemnet (GRE).
Figure 3. Figure 3.

The deduced amino acid structure for zinc finger domains of thyroid hormone receptor β are shown. Bold face type indicates amino acids common to estrogen, glucocorticoid, and thyroid hormone receptors. Short sequences of amino acids determine binding‐site recognition (binding‐site specificity or P box) and receptor‐receptor interactions (dimerization or D box).

Adapted from Brent 14, with permission
Figure 4. Figure 4.

The wild‐type thyroid hormone response elements for a number of genes are shown. Genes positively regulated by thyroid hormone include rat GH (rGH), rat α myosin heavy chain (r α MHC), bovine GH (bGH), rat malic enzyme, and chicken lysozyme silencer. Genes negatively regulated by thyroid hormone include rat thyrotropin β subunit (r TSH β Sub), rat α subunit (r α Sub), and human α subunit (h α Sub). The arrows show sequences matching 4 of 6 bases for the consensus sequence A/G TTCA. The line over the r TSH β Sub element is a sequence shown to bind thyroid hormone receptor and confer negative regulation on a heterologous promoter, but it does not match a known consensus sequence.
Figure 5. Figure 5.

A sequence comparison of the 5′‐flanking regions from the bovine GH (bGH, −193 to −125), rat GH (rGH, −197 to −129), and human GH (hGH, −194 to −126) genes. The sequences are aligned around a 38 bp sequence at approximately −140 with a >90% nucleotide identity among the different species of promoters. A portion of this region important for binding of the Pit‐1 transcription factor is shown to the right. A comparison of the nucleotide identity of the bGH and hGH sequences with that of the rGH seqence is shown by vertical lines. The rGH and bGH promoters are induced by T3, and the region of the bGH (‐175 to −163) and rGH (‐189 to −167) thyroid hormone response elements (TRE) are shown. The arrows indicate binding half‐sites as described in Figures 1, 2, and 4. The hGH promoter has very little sequence similarity to the other two promoters in this region, which is consistent with the absence of a thyroid hormone response.
Figure 6. Figure 6.

The levels of mRNA from Northern blot analysis (in relative optical density units) in the developing rat brain are shown for calbindin (A), myoinositol‐1,4,5‐triphosphate receptor (B), Purkinje cell protein‐2 (C), and myelin basic protein (D). The levels are compared in hypothyroid rats, with (solid circles) and without (open circles) triiodothyronine treatment.

Used by permission from 131 K. A. Strait, L. Zou, and J. H. Oppenheimer. β1 isoform‐specific regulation of a triiodothyronine‐induced gene during cerebellar development; Mol. Endocrinol. 6:1874–1880, 1992; © The Endocrine Society
Figure 7. Figure 7.

The two pathways of thyroid hormone metabolism are shown. Thyroxine is activated to triiodothyronine by removal of the 5′, outer ring, iodine atom. Thyroxine is inactivated to reverse triiodothyronine by removal of the 5, inner ring, iodine atom.
Figure 8. Figure 8.

The effect of thyroid hormone on growth (length) is shown for a patient with resistance to thyroid hormone (RTH). Thyroxine treatment [0.2–0.3 mg levothyroxine (L‐T4) per day] was started at age 3 months with a therapeutic goal of normalizing serum TSH. The child was in the third to tenth percentile prior to thyroxine treatment and increased to the tenth to twentieth percentile by the age of 2 years.

From Weiss and Refetoff 143 with permission


Figure 1.

The thyroid hormone receptor (TR) complexes that bind to specific DNA sequences, the thyroid hormone response elements (TREs), located upstream of the transcription start site (shown by arrow), are shown. These complexes confer positive and negative gene regulation. The TR can bind as a homodimer, monomer, or a heterodimer with the 9‐cis retinoic acid (9‐cis RA) receptor (RXR). The various combinations are shown for products of the TRα and TRβ genes, as well as of the RXR α, β and γ genes. All of these complexes have been demonstrated in vitro, but there are likely to be preferential in vivo interactions. The preferential binding site configurations are shown for homodimers (inverted palindrome with a 6 bp gap), monomer (single half‐site), and TR/RXR heterodimer (direct repeat with 4 bp gap). These TRE arrangements are detailed in Figure 2.



Figure 2.

The three major patterns of 6 bp half‐site sequences for thyroid hormone response elements (TREs) are shown, including a direct repeat with a 4 bp gap, an inverted palindrome with a 6 bp gap, and a palindrome. Wild‐type elements show some variation in sequence and in spacing relative to the idealized element. The influence of spacing on the direct repeat element is shown for the retinoic acid receptor (RAR), thyroid hormone receptor (TR), vitamin D receptor (VDR), 9‐cis retinoic acid receptor (RXR), and the peroxisome proliferator–activated receptor (PPAR). Palindromic elements are shown for the estrogen response element (ERE) and the glucocorticoid response elemnet (GRE).



Figure 3.

The deduced amino acid structure for zinc finger domains of thyroid hormone receptor β are shown. Bold face type indicates amino acids common to estrogen, glucocorticoid, and thyroid hormone receptors. Short sequences of amino acids determine binding‐site recognition (binding‐site specificity or P box) and receptor‐receptor interactions (dimerization or D box).

Adapted from Brent 14, with permission


Figure 4.

The wild‐type thyroid hormone response elements for a number of genes are shown. Genes positively regulated by thyroid hormone include rat GH (rGH), rat α myosin heavy chain (r α MHC), bovine GH (bGH), rat malic enzyme, and chicken lysozyme silencer. Genes negatively regulated by thyroid hormone include rat thyrotropin β subunit (r TSH β Sub), rat α subunit (r α Sub), and human α subunit (h α Sub). The arrows show sequences matching 4 of 6 bases for the consensus sequence A/G TTCA. The line over the r TSH β Sub element is a sequence shown to bind thyroid hormone receptor and confer negative regulation on a heterologous promoter, but it does not match a known consensus sequence.



Figure 5.

A sequence comparison of the 5′‐flanking regions from the bovine GH (bGH, −193 to −125), rat GH (rGH, −197 to −129), and human GH (hGH, −194 to −126) genes. The sequences are aligned around a 38 bp sequence at approximately −140 with a >90% nucleotide identity among the different species of promoters. A portion of this region important for binding of the Pit‐1 transcription factor is shown to the right. A comparison of the nucleotide identity of the bGH and hGH sequences with that of the rGH seqence is shown by vertical lines. The rGH and bGH promoters are induced by T3, and the region of the bGH (‐175 to −163) and rGH (‐189 to −167) thyroid hormone response elements (TRE) are shown. The arrows indicate binding half‐sites as described in Figures 1, 2, and 4. The hGH promoter has very little sequence similarity to the other two promoters in this region, which is consistent with the absence of a thyroid hormone response.



Figure 6.

The levels of mRNA from Northern blot analysis (in relative optical density units) in the developing rat brain are shown for calbindin (A), myoinositol‐1,4,5‐triphosphate receptor (B), Purkinje cell protein‐2 (C), and myelin basic protein (D). The levels are compared in hypothyroid rats, with (solid circles) and without (open circles) triiodothyronine treatment.

Used by permission from 131 K. A. Strait, L. Zou, and J. H. Oppenheimer. β1 isoform‐specific regulation of a triiodothyronine‐induced gene during cerebellar development; Mol. Endocrinol. 6:1874–1880, 1992; © The Endocrine Society


Figure 7.

The two pathways of thyroid hormone metabolism are shown. Thyroxine is activated to triiodothyronine by removal of the 5′, outer ring, iodine atom. Thyroxine is inactivated to reverse triiodothyronine by removal of the 5, inner ring, iodine atom.



Figure 8.

The effect of thyroid hormone on growth (length) is shown for a patient with resistance to thyroid hormone (RTH). Thyroxine treatment [0.2–0.3 mg levothyroxine (L‐T4) per day] was started at age 3 months with a therapeutic goal of normalizing serum TSH. The child was in the third to tenth percentile prior to thyroxine treatment and increased to the tenth to twentieth percentile by the age of 2 years.

From Weiss and Refetoff 143 with permission
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Article Title: Regulation of Gene Expression by Thyroid Hormones: Relation to Growth and Development
 

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Gregory A. Brent. Regulation of Gene Expression by Thyroid Hormones: Relation to Growth and Development. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 757-781. First published in print 1999. doi: 10.1002/cphy.cp070524