Gene expression and functional studies on psoriatic epidermis

Mari Hannele Tervaniemi

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Psoriasis is a common skin disorder that is characterized by thickening of the most superficial layer of the skin, the epidermis, and accumulation of white blood cells, inflammation. The exact mechanism of how psoriasis develops is still unknown. Several gene expression studies have been conducted on psoriatic skin. Most of them, however, have focused on the expression in both the epidermis and dermis or were analyzed by microarrays. Here we used a novel approach to decipher the gene expression profile of the psoriatic skin, by utilizing a more specific and sensitive detection of transcripts by RNA sequencing (RNA-seq), implemented with an improved normalization method, and combined with samples that contain mainly the skin layer of interest: the epidermis. RNA-seq revealed more accurate expression profiles in different sample types that had varying amount of total mRNA per cell. Comparison with previous transcriptomics studies on psoriasis revealed that our approach provided more information about the transcriptional dysregulation in the epidermis. The expression profiling of epidermis highlighted the involvement of innate immunity and provided, for example, deeper understanding about the components of NOD-like receptor signaling pathway and inflammasome activation in keratinocytes. Some of the components have been associated with psoriasis in previous studies, yet the exact composition and activation mechanisms of inflammasomes have remained unclear. Our RNA-seq findings thus strengthen the role of keratinocytes as modulators of inflammation in the psoriatic lesions. The improved methods and focused analysis might help to pinpoint the most important pathways and functions, including broader knowledge in the involved components, in the psoriatic lesions. This, in turn, might improve the production of more specific treatments for psoriasis. The psoriasis candidate gene CCHCR1 is located in the major psoriasis predisposition locus PSORS1, contains a psoriasis-associated risk allele *WWCC, and its gene product is expressed by the basal keratinocytes of the epidermis and has been shown to have an effect on cell proliferation and differentiation. The gene has two different transcription start sites and is able to encode for a peptide with a longer N-terminus from the transcript 1, which, however, depends upon a SNP that encodes for either tryptophan or stop codon, therefore either enabling or disabling the production of the longer protein. Here we presented association of the stop codon-encoding SNP (named as *Iso3) with psoriasis in family trios. We detected that CCHCR1 localizes at the centrosome and P-bodies, and reported isoform-specific effects on the localization of the P-bodies. Our experiments exhibited haplotype-specific effects of CCHCR1 also on cytoskeletal organization and cell proliferation; functions relevant to the pathogenesis of psoriasis. Furthermore, our results suggest that CCHCR1 might function in EGFR-STAT3 signaling and innate immunity, which strengthens the role of innate immunity in psoriasis even further. In addition, RNA-seq revealed isoform- and haplotype-specific effects on the expression profiles of different CCHCR1 cell lines. Interestingly, the most dramatic changes in gene expressions were observed in the isoform 3 -overexpressing cells but also the Non-risk and Risk haplotypes had antagonistic effects. The observation that CCHCR1 influences multiple cell signaling pathways may result from its possible role as a centrosomal P-body protein, which suggests a role in post-transcriptional regulation as well as a role in the regulation of cell cycle. Its exact function in these cellular compartments and effect in psoriatic lesions remains to be studied further.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-2430-2
Electronic ISBNs978-951-51-2431-9
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3111 Biomedicine

Cite this

Tervaniemi, M. H. (2016). Gene expression and functional studies on psoriatic epidermis. Helsinki: University of Helsinki.
Tervaniemi, Mari Hannele. / Gene expression and functional studies on psoriatic epidermis. Helsinki : University of Helsinki, 2016. 86 p.
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title = "Gene expression and functional studies on psoriatic epidermis",
abstract = "Psoriasis is a common skin disorder that is characterized by thickening of the most superficial layer of the skin, the epidermis, and accumulation of white blood cells, inflammation. The exact mechanism of how psoriasis develops is still unknown. Several gene expression studies have been conducted on psoriatic skin. Most of them, however, have focused on the expression in both the epidermis and dermis or were analyzed by microarrays. Here we used a novel approach to decipher the gene expression profile of the psoriatic skin, by utilizing a more specific and sensitive detection of transcripts by RNA sequencing (RNA-seq), implemented with an improved normalization method, and combined with samples that contain mainly the skin layer of interest: the epidermis. RNA-seq revealed more accurate expression profiles in different sample types that had varying amount of total mRNA per cell. Comparison with previous transcriptomics studies on psoriasis revealed that our approach provided more information about the transcriptional dysregulation in the epidermis. The expression profiling of epidermis highlighted the involvement of innate immunity and provided, for example, deeper understanding about the components of NOD-like receptor signaling pathway and inflammasome activation in keratinocytes. Some of the components have been associated with psoriasis in previous studies, yet the exact composition and activation mechanisms of inflammasomes have remained unclear. Our RNA-seq findings thus strengthen the role of keratinocytes as modulators of inflammation in the psoriatic lesions. The improved methods and focused analysis might help to pinpoint the most important pathways and functions, including broader knowledge in the involved components, in the psoriatic lesions. This, in turn, might improve the production of more specific treatments for psoriasis. The psoriasis candidate gene CCHCR1 is located in the major psoriasis predisposition locus PSORS1, contains a psoriasis-associated risk allele *WWCC, and its gene product is expressed by the basal keratinocytes of the epidermis and has been shown to have an effect on cell proliferation and differentiation. The gene has two different transcription start sites and is able to encode for a peptide with a longer N-terminus from the transcript 1, which, however, depends upon a SNP that encodes for either tryptophan or stop codon, therefore either enabling or disabling the production of the longer protein. Here we presented association of the stop codon-encoding SNP (named as *Iso3) with psoriasis in family trios. We detected that CCHCR1 localizes at the centrosome and P-bodies, and reported isoform-specific effects on the localization of the P-bodies. Our experiments exhibited haplotype-specific effects of CCHCR1 also on cytoskeletal organization and cell proliferation; functions relevant to the pathogenesis of psoriasis. Furthermore, our results suggest that CCHCR1 might function in EGFR-STAT3 signaling and innate immunity, which strengthens the role of innate immunity in psoriasis even further. In addition, RNA-seq revealed isoform- and haplotype-specific effects on the expression profiles of different CCHCR1 cell lines. Interestingly, the most dramatic changes in gene expressions were observed in the isoform 3 -overexpressing cells but also the Non-risk and Risk haplotypes had antagonistic effects. The observation that CCHCR1 influences multiple cell signaling pathways may result from its possible role as a centrosomal P-body protein, which suggests a role in post-transcriptional regulation as well as a role in the regulation of cell cycle. Its exact function in these cellular compartments and effect in psoriatic lesions remains to be studied further.",
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Gene expression and functional studies on psoriatic epidermis. / Tervaniemi, Mari Hannele.

Helsinki : University of Helsinki, 2016. 86 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Gene expression and functional studies on psoriatic epidermis

AU - Tervaniemi, Mari Hannele

N1 - M1 - 86 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - Psoriasis is a common skin disorder that is characterized by thickening of the most superficial layer of the skin, the epidermis, and accumulation of white blood cells, inflammation. The exact mechanism of how psoriasis develops is still unknown. Several gene expression studies have been conducted on psoriatic skin. Most of them, however, have focused on the expression in both the epidermis and dermis or were analyzed by microarrays. Here we used a novel approach to decipher the gene expression profile of the psoriatic skin, by utilizing a more specific and sensitive detection of transcripts by RNA sequencing (RNA-seq), implemented with an improved normalization method, and combined with samples that contain mainly the skin layer of interest: the epidermis. RNA-seq revealed more accurate expression profiles in different sample types that had varying amount of total mRNA per cell. Comparison with previous transcriptomics studies on psoriasis revealed that our approach provided more information about the transcriptional dysregulation in the epidermis. The expression profiling of epidermis highlighted the involvement of innate immunity and provided, for example, deeper understanding about the components of NOD-like receptor signaling pathway and inflammasome activation in keratinocytes. Some of the components have been associated with psoriasis in previous studies, yet the exact composition and activation mechanisms of inflammasomes have remained unclear. Our RNA-seq findings thus strengthen the role of keratinocytes as modulators of inflammation in the psoriatic lesions. The improved methods and focused analysis might help to pinpoint the most important pathways and functions, including broader knowledge in the involved components, in the psoriatic lesions. This, in turn, might improve the production of more specific treatments for psoriasis. The psoriasis candidate gene CCHCR1 is located in the major psoriasis predisposition locus PSORS1, contains a psoriasis-associated risk allele *WWCC, and its gene product is expressed by the basal keratinocytes of the epidermis and has been shown to have an effect on cell proliferation and differentiation. The gene has two different transcription start sites and is able to encode for a peptide with a longer N-terminus from the transcript 1, which, however, depends upon a SNP that encodes for either tryptophan or stop codon, therefore either enabling or disabling the production of the longer protein. Here we presented association of the stop codon-encoding SNP (named as *Iso3) with psoriasis in family trios. We detected that CCHCR1 localizes at the centrosome and P-bodies, and reported isoform-specific effects on the localization of the P-bodies. Our experiments exhibited haplotype-specific effects of CCHCR1 also on cytoskeletal organization and cell proliferation; functions relevant to the pathogenesis of psoriasis. Furthermore, our results suggest that CCHCR1 might function in EGFR-STAT3 signaling and innate immunity, which strengthens the role of innate immunity in psoriasis even further. In addition, RNA-seq revealed isoform- and haplotype-specific effects on the expression profiles of different CCHCR1 cell lines. Interestingly, the most dramatic changes in gene expressions were observed in the isoform 3 -overexpressing cells but also the Non-risk and Risk haplotypes had antagonistic effects. The observation that CCHCR1 influences multiple cell signaling pathways may result from its possible role as a centrosomal P-body protein, which suggests a role in post-transcriptional regulation as well as a role in the regulation of cell cycle. Its exact function in these cellular compartments and effect in psoriatic lesions remains to be studied further.

AB - Psoriasis is a common skin disorder that is characterized by thickening of the most superficial layer of the skin, the epidermis, and accumulation of white blood cells, inflammation. The exact mechanism of how psoriasis develops is still unknown. Several gene expression studies have been conducted on psoriatic skin. Most of them, however, have focused on the expression in both the epidermis and dermis or were analyzed by microarrays. Here we used a novel approach to decipher the gene expression profile of the psoriatic skin, by utilizing a more specific and sensitive detection of transcripts by RNA sequencing (RNA-seq), implemented with an improved normalization method, and combined with samples that contain mainly the skin layer of interest: the epidermis. RNA-seq revealed more accurate expression profiles in different sample types that had varying amount of total mRNA per cell. Comparison with previous transcriptomics studies on psoriasis revealed that our approach provided more information about the transcriptional dysregulation in the epidermis. The expression profiling of epidermis highlighted the involvement of innate immunity and provided, for example, deeper understanding about the components of NOD-like receptor signaling pathway and inflammasome activation in keratinocytes. Some of the components have been associated with psoriasis in previous studies, yet the exact composition and activation mechanisms of inflammasomes have remained unclear. Our RNA-seq findings thus strengthen the role of keratinocytes as modulators of inflammation in the psoriatic lesions. The improved methods and focused analysis might help to pinpoint the most important pathways and functions, including broader knowledge in the involved components, in the psoriatic lesions. This, in turn, might improve the production of more specific treatments for psoriasis. The psoriasis candidate gene CCHCR1 is located in the major psoriasis predisposition locus PSORS1, contains a psoriasis-associated risk allele *WWCC, and its gene product is expressed by the basal keratinocytes of the epidermis and has been shown to have an effect on cell proliferation and differentiation. The gene has two different transcription start sites and is able to encode for a peptide with a longer N-terminus from the transcript 1, which, however, depends upon a SNP that encodes for either tryptophan or stop codon, therefore either enabling or disabling the production of the longer protein. Here we presented association of the stop codon-encoding SNP (named as *Iso3) with psoriasis in family trios. We detected that CCHCR1 localizes at the centrosome and P-bodies, and reported isoform-specific effects on the localization of the P-bodies. Our experiments exhibited haplotype-specific effects of CCHCR1 also on cytoskeletal organization and cell proliferation; functions relevant to the pathogenesis of psoriasis. Furthermore, our results suggest that CCHCR1 might function in EGFR-STAT3 signaling and innate immunity, which strengthens the role of innate immunity in psoriasis even further. In addition, RNA-seq revealed isoform- and haplotype-specific effects on the expression profiles of different CCHCR1 cell lines. Interestingly, the most dramatic changes in gene expressions were observed in the isoform 3 -overexpressing cells but also the Non-risk and Risk haplotypes had antagonistic effects. The observation that CCHCR1 influences multiple cell signaling pathways may result from its possible role as a centrosomal P-body protein, which suggests a role in post-transcriptional regulation as well as a role in the regulation of cell cycle. Its exact function in these cellular compartments and effect in psoriatic lesions remains to be studied further.

KW - Apoptosis

KW - Carrier Proteins

KW - Cell Differentiation

KW - Cell Proliferation

KW - Centrosome

KW - Cytoskeleton

KW - Epidermal Growth Factor

KW - Epidermis

KW - Gene Expression

KW - Gene Expression Regulation, Developmental

KW - Inflammasomes

KW - Intracellular Signaling Peptides and Proteins

KW - +genetics

KW - +metabolism

KW - Keratinocytes

KW - +cytology

KW - Polymorphism, Single Nucleotide

KW - Psoriasis

KW - RNA

KW - Sequence Analysis, RNA

KW - Signal Transduction

KW - Skin

KW - STAT3 Transcription Factor

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-2430-2

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Tervaniemi MH. Gene expression and functional studies on psoriatic epidermis. Helsinki: University of Helsinki, 2016. 86 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 60/2016 ).