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Title: A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation}
Article:
Abstract:
Hereditary nasal parakeratosis( HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study( GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2( praw = 4. 4×10−14). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1. 6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38× coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9( H3K9) methyltransferase, which mediates chromatin silencing. The variant c. 972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme( p. N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.
Introduction:
The outermost layer of the skin, the epidermis, is a stratified squamous epithelium which forms a barrier against the environment. It is renewed throughout lifetime by continuous proliferation of keratinocytes in the lower layers of the epithelium juxtaposed to a basement membrane. Once the cells exit the cell cycle, they start to move outwards and go on to differentiate while building up the stratified architecture of the epidermis. Epidermal renewal is a tightly controlled process that relies on well-orchestrated and finely tuned changes in the expression of genes encoding cell cycle regulators and structural components such as keratins or adhesion molecules. In their final stage of terminal differentiation, the keratinocytes lose their nuclei and cytoplasmic organelles to become corneocytes, which form the outermost tightly sealing layer of the epidermis. Corneocytes from the surface of the epidermis will eventually be sloughed into the environment. A complete turnover of the nonglabrous epidermis takes about 40–56 days in healthy humans, 8–10 days in mice and about 22 days in dogs[1],[2]. Much progress has been made in the understanding of gene expression in keratinocytes during all stages of differentiation and a number of involved signaling pathways are now known[3]–[5]. The overall differentiation program of keratinocytes follows a cline of very active global transcription in the basal cells towards more and more restricted transcription profiles in further differentiated cells. There is increasing evidence that epigenetic processes such as DNA methylation and histone modifications play an important role in the gradual transcriptional silencing during keratinocyte differentiation[6]. Spontaneous animal mutants with hereditary defects in the normal differentiation of the epidermis provide an opportunity to identify further components of the complex regulatory network required to establish specific patterns of gene expression. Due to their special population structure purebred dogs are particularly well suited for genetic analysis[7]. Successful examples for the utilization of dog genetics in skin research include the identification of genes involved in the determination of hair characteristics[8], ectodermal development[9], one form of ichthyosis[10], congenital keratoconjunctivitis sicca and ichthyosiform dermatosis[11], and the excessive skin folding in Chinese Shar Pei dogs[12]. Hereditary nasal parakeratosis( HNPK) of Labrador Retrievers has been reported to consist of a defect in the differentiation of the specialized epidermis of the nasal planum[13],[14]. HNPK affected dogs develop crusts and fissuring of the nasal planum at a young age but are otherwise healthy. The pathognomonic histopathological changes consist of a marked diffuse parakeratotic hyperkeratosis characterized by the retention of nuclei in the stratum corneum and an accumulation of proteinaceous fluid( “serum lakes”) within the stratum corneum( Fig. S1). HNPK is inherited as a monogenic autosomal recessive trait and has so far exclusively been described in the Labrador Retriever breed[13]. In this study we used a genome-wide association study( GWAS) and whole genome re-sequencing approach( WGS) of an affected Labrador Retriever to identify the genetic lesion responsible for HNPK.
Discussion:
In this study we identified a missense variant of SUV39H2 as candidate causative genetic defect for HNPK in Labrador Retrievers. It has to be cautioned that our analysis focused on non-synonymous variants. We thus cannot formally rule out the possibility that a synonymous or non-coding regulatory variant in absolute linkage disequilibrium with the SUV39H2:c. 972T>G variant is the actual causative variant. However, the strictly recessive mode of inheritance suggests a complete loss-of-function allele, which excludes a large fraction of regulatory variants with minor effects. It also has to be considered that our variant detection relied on short read mapping to an imperfect reference genome. Thus, we will have missed variants, which are located in genome segments that are not contained in the reference genome, such as gap regions. We may also have missed non-synonymous variants in genes that are not or not correctly annotated in the dog reference genome. The identified missense variant is actually within a plausible functional candidate gene. SUV39H2 catalyzes the addition of methyl groups to the lysine 9 residue of histone 3( H3K9) and transforms an unmethylated H3K9 into trimethylated H3K9me3[19]. Methylation of H3K9 is a chromatin modification inducing transcriptional silencing and a typical hallmark of heterochromatin[20]. The crystal structure of SUV39H2 has been solved and the catalytically active site for the methyltransferase activity is located within the so-called SET domain[21]. As the SUV39H2:p. N324K variant in HNPK affected Labrador Retrievers affects a highly conserved amino acid residue within this SET domain it is conceivable that this variant abolishes SUV39H2 function completely or to a large extent. While there is extensive knowledge on the biochemical activity of SUV39H2 and its role in heterochromatin formation, its specific physiological function in vivo is much less clear. Addressing this question has been difficult as mammals express a large number of closely related histone modifying enzymes including eight genes encoding specific H3K9 methyltransferases[21]. Suv39h2 deficient mice and mice deficient in the closely related Suv39h1 do not display any obvious phenotype[22]. However, alterations in the nasal planum have not been specifically evaluated in these mice. In contrast, the double knockout mice deficient in both Suv39h1 and Suv39h2 exhibit severe deficiencies in genome stability and regulation of telomere length. Consequently, the double knockout mice have a greatly impaired viability and delayed growth[22],[23]. These data suggest that Suv39h2 deficient mice do not display an overt phenotype as the Suv39h2 function may be replaced by other redundant H3K9 methyltransferases. The clinical symptoms of HNPK in Labrador Retrievers are exclusively restricted to the epidermis of the nasal planum. It is currently unclear why a defect in a broadly expressed histone modifying enzyme leads to a very tissue-specific clinical phenotype. We speculate that this may be due to the tissue-specific expression profiles of the partially redundant H3K9 methyltransferases, with the epidermis of the nasal planum being the only tissue where the loss of SUV39H2 cannot be compensated. We also cannot explain at this point why Suv39h2 deficient mice do not display a similar phenotype. However, it can be argued that the nasal planum of mice is extraordinarily small and that subtle alterations are very difficult to assess. Our morphological analyses clearly demonstrate that the HNPK phenotype is not due to hyperproliferation of keratinocytes. Thus, it seems highly probable that the HNPK phenotype is caused by an altered terminal keratinocyte differentiation. Similar expression patterns of the differentiation marker DSG1 in cases and control dogs provide further evidence that this delay in differentiation might be primarily localized in the outermost layers of the epidermis. SUV39H2, a chromatin modifying enzyme, is a logical candidate for being involved in the regulation of cell differentiation. Although we do not yet have complete functional proof for its role in keratinocyte differentiation, our genetic data together with the detailed in vivo histopathological analyses strongly suggest that SUV39H2:p. N324K is the causative defect for HNPK. Further studies with additional differentiation markers and RNA-seq experiments will help to clarify which downstream effector molecules are altered by the lacking chromatin modification in SUV39H2 deficient cells resulting in an impaired keratinocyte differentiation process. In conclusion, we have identified a missense variant in the histone methylase SUV39H2 as most likely causative for HNPK in Labrador Retrievers. This provides a first indication of an involvement of this particular enzyme in the epigenetic regulation of keratinocyte differentiation.
Hereditary nasal parakeratosis ( HNPK ) , an inherited monogenic autosomal recessive skin disorder , leads to crusts and fissures on the nasal planum of Labrador Retrievers . We performed a genome-wide association study ( GWAS ) and mapped the causative mutation to a small interval on chromosome 2 . We re-sequenced the entire genome of one HNPK affected dog and detected three protein-changing mutations in the critical interval . We genotyped these three variants in larger cohorts of dogs and only one showed perfect genotype-phenotype association , prompting us to consider this variant , a missense mutation in SUV39H2 , as the most likely causative variant for HNPK . SUV39H2 is an enzyme involved in histone methylation and epigenetic silencing , a process determining the regulation of gene expression during keratinocyte differentiation . A loss of SUV39H2 function is predicted to result in delayed differentiation , which is compatible with the histopathological changes that we observed in biopsies from nasal epidermis of HNPK affected Labrador Retrievers . Thus , our results provide the most likely causative mutation for a hereditary disease in dogs that can now be eradicated by selective breeding . In addition , our results also provide the first hint that SUV39H2 , whose in vivo function is not fully understood , may be involved in keratinocyte differentiation .