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Vol. 15, No. 20, pp. 2687-2701, October 15, 2001
1 Kennedy Krieger Research Institute and
2 Department of Neuroscience, 3 Graduate Program in
Human Genetics, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205, USA
The mammalian hairless (hr) gene plays a critical
role in the maintenance of hair growth. Although the hr gene
has been identified, the biochemical function of its encoded protein
(Hr) has remained obscure. Here, we show that Hr functions as a
transcriptional corepressor for thyroid hormone receptors (TRs). We
find that two independent regions of Hr mediate TR binding and that
interaction requires a cluster of hydrophobic residues similar to the
binding motifs proposed for nuclear receptor corepressors (N-CoR and
SMRT). Similarly, we show that Hr binds to the same region of TR as
known corepressors. We show that Hr interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies,
indicating that the mechanism of Hr-mediated repression is likely
through associated HDAC activity. Thus, Hr is a component of the
corepressor machinery, and despite its lack of sequence identity with
previously described corepressors, its mode of action is remarkably
conserved. On the basis of its thyroid hormone-inducible and tissue-
and developmental-specific expression, Hr likely defines a new class of
nuclear receptor corepressors that serve a more specialized role than
ubiquitous corepressors. The discovery that Hr is a corepressor
provides a molecular basis for specific hair loss syndromes in both
humans and mice.
[Key Words: Nuclear receptor; thyroid hormone; transcriptional repression; histone deacetylase]
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