The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

Abstract

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.

Roles of jumonji and jumonji family genes in chromatin regulation and development

“…Hairless functions as a nuclear receptor corepressor (Potter et al, 2001). In addition, mouse Jmj protein was shown to be a transcriptional repressor that directly represses cyclin D1 expression (Toyoda et al, 2003).…”

“…Hairless protein functions as a nuclear receptor corepressor and interacts with multiple nuclear receptors such as thyroid hormone receptor, retinoic acid receptor-related orphan receptor ␣, and vitamin D receptor (Potter et al, 2001;Moraitis et al, 2002;Hsieh et al, 2003). Hairless represses transcriptional activities in the context of these nuclear receptors (Potter et al, 2001;Moraitis et al, 2002;Hsieh et al, 2003).…”

“…Hairless represses transcriptional activities in the context of these nuclear receptors (Potter et al, 2001;Moraitis et al, 2002;Hsieh et al, 2003). Of interest, Hairless as well as Jmj have transcriptional repression activity, although these two proteins might not have 2-OG-Fe(II)-dependent histone demethylase activity, because cofactor binding sites are not conserved (Fig.…”

The hairless (hr) gene is involved in the congenital hypotrichosis of Valle del Belice sheep

“…Potter et al [13] demonstrated that the Hr protein encoded by the hairless gene functions as a transcriptional corepressor for thyroid hormone receptor (TR). Hr binds to TR and interacts with histone deacetylases.…”

“…The gene is highly conserved between men, mice and rats [1,2,6]. The protein codified by this gene is a transcriptional corepressor for thyroid hormone receptors [13]. This gene is highly expressed in the brain and skin [1,4].…”