HOXC13 Is Involved in the Regulation of Human Hair Keratin Gene Expression

Luis Felipe Jave-Suarez,Hermelita Winter,Lutz Langbein,Michael A Rogers,Jürgen Schweizer

doi:10.1074/jbc.m101616200

Luis Felipe Jave-Suarez, Hermelita Winter + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m101616200

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Abstract

At present, HOXC13 is the only member of the HOX multigene family that produces a fragile hair phenotype when mutated or overexpressed in mice. To determine whether hair keratin genes are targets for this transcription factor, we analyzed the HOXC13 responsiveness of human hair keratin genes, whose expression matched that of nuclear HOXC13, immunologically revealed in cells of the lower hair-forming compartment of the human anagen hair follicle. We show that HOXC13, but not a homeobox-deleted HOXC13, strongly activated the promoters of the genes, with the respective proximal promoter regions being sufficient for optimal activation. The hair keratin promoters contained numerous putative Hox binding core motifs TAAT, TTAT, and TTAC. Electrophoretic mobility shift assays revealed that HOXC13 bound exclusively to distinct TAAT and TTAT core motifs that were clearly concentrated in the proximal promoter regions. A comparison of the sequences flanking HOXC13 binding and nonbinding core motifs, respectively, allowed the deduction of an extended 8-bp HOXC13 consensus binding sequence TT(A/T)ATNPuPu. Thus, the DNA binding conditions for HOXC13 were distinct from those of other members of the paralogous group 13, i.e. murine Hoxb13 and HOXd13, for which previous investigations yielded the consensus binding sequence TTTA(T/C)NPuPu. Collectively, our data speak for a direct involvement of HOXC13 in the control of hair keratin expression during early trichocyte differentiation.

Highlights

Hox genes encode evolutionarily conserved transcription factors that are important gene regulators involved in cell fate determination during embryonic development
Our laboratory has elucidated the organization of the human type I and type II hair keratin gene loci and characterized the sequential expression of their members during trichocyte differentiation (12–15) Based on this knowledge, we selected three human type I hair keratin genes hHa5, hHa2, and hHa7 as well as the transcribed pseudogene ␸hHaA, whose mRNA expression patterns in the lower hair forming compartment of the human hair follicle (13, 16) corresponded to that described for Hoxc13 in mouse hair follicles (6), and investigated whether they are target genes for HOXC13
We provide strong evidence that these hair keratin genes are transcriptionally up-regulated by HOXC13 primarily via binding of the transcription factor to distinct core recognition motifs, TAAT and TTAT, in the respective proximal promoters

Summary

Introduction

Hox genes encode evolutionarily conserved transcription factors that are important gene regulators involved in cell fate determination during embryonic development. Most of these Hoxc expressing anatomical regions are known sites of hair keratin synthesis (9, 10 and references therein), it has been hypothesized that Hoxc might possess special functions in hair and filiform papillae development by being involved in the control of hair keratin gene expression (6 – 8). In line with this assumption, recent investigations in Hoxc13-overexpressing mice have shown that a variety of hair follicle-specific genes are regulated by this transcription factor (11). We provide strong evidence that these hair keratin genes are transcriptionally up-regulated by HOXC13 primarily via binding of the transcription factor to distinct core recognition motifs, TAAT and TTAT, in the respective proximal promoters

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