Hormonal Regulation of Gene Expression 
William W. Chin, M.D. — Investigator 
Dr. Chin is also Associate Professor of Medicine at Harvard Medical School and Physician at Brigham and 
Women's Hospital, Boston. He obtained his undergraduate degree in chemistry from Columbia College 
and his M.D. degree from Harvard Medical School. His postdoctoral work was performed with Jacob Maizel 
and Philip Leder at the NIH and with Joel Habener at the Massachusetts General Hospital. His awards 
include the Bowditch Lectureship Award of the American Physiological Association, the Van Meter- USV 
Award of the American Thyroid Association, and the Outstanding Investigator's Award from the American 
Federation for Clinical Research. 
HORMONES, key players in the endocrine and 
nervous systems, are produced by specific 
tissues in the body, effect extracellular communi- 
cation, and regulate cellular function. Our stud- 
ies have focused on the hormonal regulation of 
gene expression and on several genes that encode 
the hormones themselves. 
Thyroid Hormone Regulation of TSH 
Gene Expression 
Thyrotropin (TSH) is a polypeptide hormone 
that is produced and secreted by a single cell type 
in the anterior pituitary gland. It comprises two 
different sugar-containing polypeptide subunits, 
a and |S, which are encoded by genes located on 
different chromosomes. Importantly, TSH stimu- 
lates the thyroid gland to produce the thyroid 
hormones, T3 and T4. These are modified amino 
acids that regulate metabolism and gene expres- 
sion in almost every cell of the body. To maintain 
a constant level of T3 and T4 in the bloodstream, 
these hormones act back on the pituitary to de- 
crease TSH production and secretion. Hence TSH 
and thyroid hormones are involved in a classic 
negative-feedback relationship. 
To understand further the molecular mecha- 
nisms involved in the negative regulation of TSH 
synthesis by thyroid hormones at the transcrip- 
tion level, we have isolated and analyzed the 
genes encoding the a- and jS-subunits of TSH in 
the rat. 
Thyroid hormones, in general, act at the cellu- 
lar level by entering the cell either as T3 or T4. 
T4 may be converted to T3 in certain tissues, such 
as the pituitary. T3 then enters the nucleus, 
where it interacts with the thyroid hormone re- 
ceptor (TR) , a protein encoded by the proto-on- 
cogene c-erbA. The T3-TR complex then binds 
directly to cis-DNA elements within thyroid hor- 
mone-responsive genes to activate the appro- 
priate responses. 
Using deletion-mutation analyses of the regula- 
tory regions of the subunit genes, we have local- 
ized putative thyroid hormone response ele- 
ments (TREs) to the 3' end of the first exon and to 
a region just 5' to this exon in the rat TSH;8 gene, 
and to a proximal upstream promoter region of 
the rat a gene. There is limited sequence similar- 
ity between these cis-DNA elements and a TRE 
defined in the rat growth hormone gene. Consis- 
tent with their roles as TREs, these DNAs bind 
TRs. Thus our studies have supported the hypoth- 
esis that thyroid hormones inhibit a and TSH|8 
gene expression by the direct binding of a T3-TR 
complex to specific areas within regulatory re- 
gions of the subunit genes and their resultant in- 
terference with transcription. 
Multiple Thyroid Hormone Receptors 
Another interest involves the elucidation of the 
trans-acting factors involved in thyroid hormone 
action. Critically important are several forms of 
the TR. These are encoded by two genes, a and /3, 
each expressing at least two related molecules 
obtained by alternative splicing. The rat TRa 
gene encodes a bona fide TR, TRal , and a related 
form, c-erbAa2, that is identical to TRal for the 
first 370 amino acids, which include the DNA- 
binding domain and much of the thyroid hor- 
mone-binding domain at the carboxyl -terminal 
end. However, carboxyl terminal to this common 
region is a divergent sequence. The c-erbAa2 
form does not bind thyroid hormone or transacti- 
vate thyroid hormone-responsive genes, but 
does bind to putative TREs in vitro, as shown by a 
DNA-binding assay. These and other results sug- 
gest that the biologically active c-erbAa2 serves 
as an inhibitor of active TR action. The rat TR|8 
gene encodes two functional TRs, TRjSl and 
TR|82. TR/31 and TR/32 are identical, from several 
amino acids amino terminal to the DNA-binding 
region to the remainder of the molecule. How- 
ever, the amino-terminal regions of the DNA- 
binding domain are different. We have shown 
that TR/32 binds hormone with the same relative 
affinities as the other receptors, binds DNA, 
and transactivates thyroid hormone-responsive 
genes. 
Surprisingly, TR/32 is expressed only in the pi- 
tuitary gland. This is remarkable because of the 
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