Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis

The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.

[1]  C. Zheng,et al.  Identification of breast cancer candidate genes using gene co-expression and protein-protein interaction information , 2016, Oncotarget.

[2]  Hui Sun,et al.  Identification of key genes associated with gastric cancer based on DNA microarray data , 2015, Oncology letters.

[3]  De-Shuang Huang,et al.  Predicting Hub Genes Associated with Cervical Cancer through Gene Co-Expression Networks , 2016, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[4]  Yang Wang,et al.  Identification of genes associated with melanoma metastasis , 2015, The Kaohsiung journal of medical sciences.

[5]  J. Little,et al.  MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project , 2015, British Journal of Cancer.

[6]  Rosa D. Hernansaiz-Ballesteros,et al.  Babelomics 5.0: functional interpretation for new generations of genomic data , 2015, Nucleic Acids Res..

[7]  D. Schadendorf,et al.  Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort , 2015, Oncotarget.

[8]  Jiali Han,et al.  MC1R variants increased the risk of sporadic cutaneous melanoma in darker‐pigmented Caucasians: A pooled‐analysis from the M‐SKIP project , 2014, International journal of cancer.

[9]  V. Swope,et al.  Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention. , 2014, Archives of biochemistry and biophysics.

[10]  Z. Abdel‐Malek,et al.  MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation , 2014, Pigment cell & melanoma research.

[11]  Michael I. Wilson,et al.  WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1 , 2014, Molecular cell.

[12]  S. Puig,et al.  Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer , 2013, Oncotarget.

[13]  Hongyu Diao,et al.  Gene Expression Profiling Combined with Bioinformatics Analysis Identify Biomarkers for Parkinson Disease , 2012, PloS one.

[14]  Simon C. Potter,et al.  Mapping cis- and trans-regulatory effects across multiple tissues in twins , 2012, Nature Genetics.

[15]  Rafael C. Jimenez,et al.  The IntAct molecular interaction database in 2012 , 2011, Nucleic Acids Res..

[16]  Livia Perfetto,et al.  MINT, the molecular interaction database: 2012 update , 2011, Nucleic Acids Res..

[17]  Jochen K. Lennerz,et al.  An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair / fair skin background , 2012 .

[18]  A. Ganesan,et al.  The pleiotropic roles of autophagy regulators in melanogenesis , 2011, Pigment cell & melanoma research.

[19]  Isei Tanida.  Autophagy basics , 2011, Microbiology and immunology.

[20]  H. Smeets,et al.  Functional annotation of heart enriched mitochondrial genes GBAS and CHCHD10 through guilt by association. , 2010, Biochemical and biophysical research communications.

[21]  Gary D. Bader,et al.  Cytoscape Web: an interactive web-based network browser , 2010, Bioinform..

[22]  S. Gygi,et al.  Network organization of the human autophagy system , 2010, Nature.

[23]  Joaquín Dopazo,et al.  SNOW, a web-based tool for the statistical analysis of protein–protein interaction networks , 2009, Nucleic Acids Res..

[24]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[25]  Eric E Schadt,et al.  Cycle Regulation in Islets with Diabetes Susceptibility a Gene Expression Network Model of Type 2 Diabetes Links Cell P

, 2008 .

[26]  Guido Kroemer,et al.  Autophagy in the Pathogenesis of Disease , 2008, Cell.

[27]  H. Araki,et al.  The role of CDK in the initiation step of DNA replication in eukaryotes , 2007, Cell Division.

[28]  S. Jentsch,et al.  PCNA, the Maestro of the Replication Fork , 2007, Cell.

[29]  E. Almaas.  Biological impacts and context of network theory , 2007, Journal of Experimental Biology.

[30]  Gabriele Ausiello,et al.  MINT: the Molecular INTeraction database , 2006, Nucleic Acids Res..

[31]  A. L. Kadekaro,et al.  MC1R and the response of melanocytes to ultraviolet radiation. , 2005, Mutation research.

[32]  K. Wakamatsu,et al.  Comparison of Structural and Chemical Properties of Black and Red Human Hair Melanosomes¶ , 2005, Photochemistry and photobiology.

[33]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[34]  Adam J. Smith,et al.  The Database of Interacting Proteins: 2004 update , 2004, Nucleic Acids Res..

[35]  T. Nemoto,et al.  The Mouse APG10 Homologue, an E2-like Enzyme for Apg12p Conjugation, Facilitates MAP-LC3 Modification* , 2003, Journal of Biological Chemistry.

[36]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[37]  Ian M. Donaldson,et al.  BIND: the Biomolecular Interaction Network Database , 2001, Nucleic Acids Res..

[38]  M de Lange,et al.  Are Twins and Singletons Comparable? A Study of Disease-related and Lifestyle Characteristics in Adult Women , 2001, Twin Research.

[39]  G J Hill,et al.  UVA, pheomelanin and the carcinogenesis of melanoma. , 2000, Pigment cell research.