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Genetically programmed changes in transcription of the novel progranulin regulator

Keller, Maria LU ; Gebhardt, Claudia ; Huth, Sandra ; Schleinitz, Dorit ; Heyne, Henrike ; Scholz, Markus ; Stumvoll, Michael ; Böttcher, Yvonne ; Tönjes, Anke and Kovacs, Peter (2020) In Journal of Molecular Medicine 98(8). p.1139-1148
Abstract

Abstract: Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and... (More)

Abstract: Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 × 10−7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10−3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P < 1 × 10−7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. Key messages: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels.rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding.PSRC1 is also epigenetically regulated in subjects with high progranulin levels.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA methylation, EMSA, Progranulin, PSRC1
in
Journal of Molecular Medicine
volume
98
issue
8
pages
10 pages
publisher
Springer
external identifiers
  • scopus:85087527143
  • pmid:32620998
ISSN
0946-2716
DOI
10.1007/s00109-020-01942-7
language
English
LU publication?
yes
id
051f419b-01d4-46e9-8d83-6c5a68506ade
date added to LUP
2020-07-17 14:18:16
date last changed
2024-05-01 13:46:57
@article{051f419b-01d4-46e9-8d83-6c5a68506ade,
  abstract     = {{<p>Abstract: Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of S<sub>all</sub> &gt; 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P &lt; 1 × 10<sup>−7</sup>) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10<sup>−3</sup>). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P &lt; 1 × 10<sup>−7</sup>). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. Key messages: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels.rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding.PSRC1 is also epigenetically regulated in subjects with high progranulin levels.</p>}},
  author       = {{Keller, Maria and Gebhardt, Claudia and Huth, Sandra and Schleinitz, Dorit and Heyne, Henrike and Scholz, Markus and Stumvoll, Michael and Böttcher, Yvonne and Tönjes, Anke and Kovacs, Peter}},
  issn         = {{0946-2716}},
  keywords     = {{DNA methylation; EMSA; Progranulin; PSRC1}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1139--1148}},
  publisher    = {{Springer}},
  series       = {{Journal of Molecular Medicine}},
  title        = {{Genetically programmed changes in transcription of the novel progranulin regulator}},
  url          = {{http://dx.doi.org/10.1007/s00109-020-01942-7}},
  doi          = {{10.1007/s00109-020-01942-7}},
  volume       = {{98}},
  year         = {{2020}},
}