Forum Hair Coloration by Gene Regulation: Fact or Fiction? Teresa Matamá, 1,2 Andreia C. Gomes, 2 and Artur Cavaco-Paulo 1, * The unravelling of hair pigmenta- tion genetics and robust delivery systems to the hair follicle (HF) will allow the development of a new class of colouring products. The challenge will be changing hair col- our from inside out by safely regu- lating the activity of target genes through the specific delivery of synthetic/natural compounds, pro- teins, genes, or small RNAs. Genetics of HF Pigmentation and Greying Pigmentation is one of the most striking phenotypic traits in humans. It has great social and psychological relevance and the possibility of controlling it has immense resonance for any individual or ethnic group. The colour of human hair, skin, and eyes is determined by the amount, type, and tissue distribution of melanin. Melanin is a complex mixture of pigmented indole-rich biopolymers that are synthesised by specialised cells called melanocytes. The main types of melanin polymer are the black-to-brown eumela- nin (highly polymerised) and the yellow- to-reddish-brown pheomelanin (lighter, less polymerised, and containing sulfur) [1]. Black hair has the highest eumelanin- to-pheomelanin ratio while red-to-yellow hairs have the lowest ratio; grey or white hairs have insignificant or no melanin at all. For more information on melanin produc- tion by melanocytes, see Box 1. Pigment synthesis, storage, and transport occur in lysosome-related organelles known as melanosomes. Although the biochemical synthesis of melanin is com- mon to all pigmented tissues, melanogen- esis is regulated differently among them. In hair, melanogenesis occurs only during the anagen (active growth) phase of the hair growth cycle in melanocytes located exclusively in the hair bulb, while in skin, for instance, melanin is constitutively pro- duced. An interesting study [2] demon- strated that [19_TD$DIFF]a SNP previously associated with blond hair in northern Europeans is responsible for a 20%[20_TD$DIFF] reduction in the activity of a tissue-specific regulatory enhancer affecting KITLG gene transcrip- tion in the HF only. Different regulatory mechanisms underlie the discrepancy between the pigmentation phenotypes of hair, skin, and eyes commonly seen in an individual. Knowing how to interfere with melanogenesis in a tissue-specific manner will thus be an invaluable cosmetic tool. Several approaches have contributed to identifying genes involved in melanin syn- thesis and in the biogenesis, transport, and distribution of melanosomes, as well as genes regulating those processes (Box 1) [3,4]. These approaches include comparative genomics of candidate genes such as those identified in animal models. By October 2011, the International Feder- ation of Pigment Cell Societies database had described 378 putative pigmentation loci for mice and their human and zebrafish homologues ( http://www.espcr.org/ micemut/). Despite the many genes already implicated in melanogenesis, those TIBTEC 1306 No. of Pages 5 Box 1. HF [18_TD$DIFF]Pigmentation Among the various cells that comprise the HF, the relevant differences seen in gene expression between pigmented and grey HFs can be related to melanocyte biology (Table I and Figure I). Microarray analysis is a powerful technique that allows a global perspective on what is occurring in a cell, tissue, or organism at a particular moment through the comparison of the levels of all mRNAs corresponding to the genes being expressed: the transcriptome. Such analysis was conducted by a research group on pigmented and white human HFs [12]. Table I. Mean [8_TD$DIFF]Fold [9_TD$DIFF]Changes in the [10_TD$DIFF]Expression of a [11_TD$DIFF]Selected [12_TD$DIFF]Group of [13_TD$DIFF]Genes that were [14_TD$DIFF]Upregulated in [15_TD$DIFF]Pigmented HFs [16_TD$DIFF]Compared with [17_TD$DIFF]White HFs [8] Gene Symbol Gene Name Mean Fold Change TYRP1 Tyrosinase-related protein 1 116.58 SILV Silver homologue (mouse) 36.21 TYR Tyrosinase (oculocutaneous albinism IA) 26.36 MLANA Melan-A 25.02 TRPM1 Transient receptor potential cation channel, subfamily M, member 1 8.58 SLC45A2 Solute carrier family 45, member 2 5.21 GPR143 G protein-coupled receptor 143 3.88 CAPN3 Calpain 3 (p94) 3.68 PLXNC1 Plexin C1 3.64 KIT v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homologue 2.81 PAX3 Paired box 3 2.23 OLFM1 Olfactomedin 1 2.06 MET Met proto-oncogene (hepatocyte growth factor receptor) 2.04 HPS1 Hermansky–Pudlak syndrome 1 1.86 OSTM1 Osteopetrosis-associated transmembrane protein 1 1.66 EDNRB Endothelin receptor type B 1.65 Trends in Biotechnology, Month Year, Vol. xx, No. yy 1