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Review
. 2012 Mar;132(3 Pt 2):923-32.
doi: 10.1038/jid.2011.436. Epub 2012 Jan 12.

Genetics and epigenetics of the skin meet deep sequence

Jeffrey B Cheng  1 , Raymond J Cho
Affiliations
Review

Genetics and epigenetics of the skin meet deep sequence

Jeffrey B Cheng et al. J Invest Dermatol. 2012 Mar.

Abstract

Rapid advances in next-generation sequencing technology are revolutionizing approaches to genomic and epigenomic studies of skin. Deep sequencing of cutaneous malignancies reveals heavily mutagenized genomes with large numbers of low-prevalence mutations and multiple resistance mechanisms to targeted therapies. Next-generation sequencing approaches have already paid rich dividends in identifying the genetic causes of dermatologic disease, both in heritable mutations and the somatic aberrations that underlie cutaneous mosaicism. Although epigenetic alterations clearly influence tumorigenesis, pluripotent stem cell biology, and epidermal cell lineage decisions, labor and cost-intensive approaches long delayed a genome-scale perspective. New insights into epigenomic mechanisms in skin disease should arise from the accelerating assessment of histone modification, DNA methylation, and related gene expression signatures.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors state no conflict of interest.

Figures

Figure 1
Figure 1. Epigenetic modifications
(a) Histone modification. Histone proteins (depicted as blue cylinders) spool DNA (depicted as yellow lines) to form nucleosomes and chromatin. Posttranslational modifications (e.g., addition of acetyl, methyl, or ubiqituin groups) to the N-terminal tail regions of histones alter local chromatin conformation. Variability in chromatin condensation affects the accessibility of genes. Loosely condensed regions (euchromatin) are more actively expressed and tightly condensed regions (heterochromatin) are repressed. Depicted in the figure is histone acetylation, associated with loosening of local chromatin and more active gene expression. (b) DNA methylation. DNA methylation occurs through the addition of a methyl group to the C5 position of cytosine to form 5-methylcytosine, typically at cytosine phosphate guanine (CpG) dinucleotides. In promoter regions, DNA methylation silences genes by interfering with transcription factor binding and/or recruitment of methyl-CpG-binding proteins that recruit repressor complexes. DNA methylation is typically associated with tightly condensed chromatin.
Figure 2
Figure 2. Rapidly expanding sequence profiles of cancer
(a) For DNA, graph depicts the number of sequenced nucleotides per $1 USD (NHGRI 2011 data sheet, www.genome.gov/sequencingcosts/). For gene expression quantification, the number of discrete assessments across all coding regions is graphed. From 2001 to 2005, the standard Affymetrix (Santa Clara, CA) platform primarily assessed expression at the 3′ ends of transcripts, reaching a maximum of B50,000 transcripts and variants per array. By 2005, so-called ‘‘exon arrays’’ were introduced, carrying probes for each individual exon, interrogating expression of more than 250,000 exons. From 2009 to present, RNA quantification has increasingly been performed using sequencing (RNAseq), approximating all >6 million coding nucleotides in the human genome. For cytosine phosphate guanine (CpG) methylation, the primary advances represent new technologies making denser assessment feasible. Individual platforms, techniques, and genomic CpG coverage are reviewed in Laird (2010) and Fouse et al. (2010). (b) Histogram of genetic heterogeneity in cancer. On the basis of recent sequencing studies, for each cancer type, a histogram of the most commonly mutated genes are arrayed from most to least frequent (The Cancer Genome Atlas Research Network, 2008, 2011; Wei et al., 2011). All non-synonymous mutations per gene were binned; copy number changes are not displayed.
Figure 3
Figure 3. Accelerating gains in correlating genotype to phenotype
(a) For chromosome 11, distribution of interrogated DNA sequence displayed for (A) microsatellite markers (1993), (B) single-nucleotide polymorphisms on Affymetrix 100K genotypic oligonucleotide array (2004), and (C) whole exome (2010). (b) Genetic bases of recent cutaneous phenotypes identified by exome sequencing Affymetrix, USA (Sun et al., 2010; Concolino et al., 2010; Wang et al., 2010; Goudie et al., 2011; Auer-Grumbach et al., 2011; Zhou et al., 2011a; Shaheen et al., 2011; Lindhurst et al., 2011; Liu et al., 2011; Cullinane et al., 2011). Closed diamonds show activating mutations; open diamonds represent loss-of-function mutations.
Figure 4
Figure 4. Histone modification and DNA methylation profile of keratin 5 (KRT5)
University of California, Santa Cruz (UCSC) genome browser snapshot encompassing an ~9 Kb segment of DNA spanning the KRT5 locus. The dark blue rectangles and lines depict the KRT5 gene structure. Profiled cells are primary cultured neonatal foreskin keratinocytes (KCs, top) and fibroblasts (bottom). These KCs express KRT5, whereas fibroblasts do not. Starting from the top, there are high levels of H3K4me3 histone modification signal (associated with active promoters) at the promoter in KCs (depicted in green). In pink, H3K27me3 signal (associated with gene repression) shows low levels in KCs. Depicted in brown are regions of methylated DNA (assessed by methylated DNA immunoprecipitation sequencing), with minimal signal in KCs and high levels in fibroblasts. Unmethylated DNA (assessed by methylation-sensitive restriction enzyme sequencing) is depicted with light blue vertical bars and shows a high number of sequencing peaks for KCs compared with a low number for fibroblasts. These data and other reference epigenomes are publicly available from the NIH Roadmap Epigenome Project website (http://vizhub.wustl.edu; Zhou et al., 2011b).
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