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MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD.

Nieratschker V, Massart R, Gilles M, Luoni A, Suderman MJ, Krumm B, Meier S, Witt SH, Nöthen MM, Suomi SJ, Peus V, Scharnholz B, Dukal H, Hohmeyer C, Wolf IA, Cirulli F, Gass P, Sütterlin MW, Filsinger B, Laucht M, Riva MA, Rietschel M, Deuschle M, Szyf M - Transl Psychiatry (2014)

Bottom Line: Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms.MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood.Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany [2] Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany.

ABSTRACT
Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

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Expanded views from the UCSC genome browser of the MORC1 gene are depicted. (a) Human CD34+ cord blood. (b) 14–30-day-old monkey CD3+ T cells (TC/D14–30), 2-year-old monkey CD3+ T cells (TC/2y). Numbers 1, 2, 3 indicate the locations of DNA amplification for QPCR validations. (c) Rat PFC. For each graph, average methylation probe fold differences (Log2) between control and ELS groups, as well as regions of significant differential methylation are shown. The last track shows the MORC1 gene, as taken from the NCBI reference sequences collection (RefSeq). QPCR analysis of DNA methylation differences in the MORC1 gene between ELS and control groups are displayed. Relative bound fraction concentrations are shown. Error bars represent s.e.m. The symbol ‘*' denotes P-values <0.05, as calculated with the Mann–Whitney U-test. Ctrl, control group; ELS, early life stress; MORC1, MORC family CW-type zinc finger 1; QPCR, quantitative PCR.
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fig1: Expanded views from the UCSC genome browser of the MORC1 gene are depicted. (a) Human CD34+ cord blood. (b) 14–30-day-old monkey CD3+ T cells (TC/D14–30), 2-year-old monkey CD3+ T cells (TC/2y). Numbers 1, 2, 3 indicate the locations of DNA amplification for QPCR validations. (c) Rat PFC. For each graph, average methylation probe fold differences (Log2) between control and ELS groups, as well as regions of significant differential methylation are shown. The last track shows the MORC1 gene, as taken from the NCBI reference sequences collection (RefSeq). QPCR analysis of DNA methylation differences in the MORC1 gene between ELS and control groups are displayed. Relative bound fraction concentrations are shown. Error bars represent s.e.m. The symbol ‘*' denotes P-values <0.05, as calculated with the Mann–Whitney U-test. Ctrl, control group; ELS, early life stress; MORC1, MORC family CW-type zinc finger 1; QPCR, quantitative PCR.

Mentions: MDD is one of the well-established ELS-associated phenotypes.1, 2, 3, 4 We therefore took advantage of a previous GWAS study on MDD36 and performed a gene-based case–control analysis to test for an association between genetic variants in those overlapping genes and MDD. We excluded U6 and 7SK from our analysis, as multiple copies of those genes exist throughout the genome. In addition, we had to exclude PRMT5 and PDE4DIP as no genetic variants in PDE4DIP and only one genetic variant in PRMT5 were represented in the quality-controlled GWAS data set. Of the remaining three genes, MORC1 and CSRNP3 showed a nominally significant association with MDD (P=0.00483 and 0.03139, respectively). Only the association of MORC1 with MDD withstood Bonferroni correction for the number of genes tested (P=0.01449), thus providing evidence that MORC1 is involved in MDD, a stress-associated disorder. QPCR was used to validate MORC1 methylation changes observed in human CD34+ cells, monkey CD3+ T cells and rat PFC (Figure 1).


MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD.

Nieratschker V, Massart R, Gilles M, Luoni A, Suderman MJ, Krumm B, Meier S, Witt SH, Nöthen MM, Suomi SJ, Peus V, Scharnholz B, Dukal H, Hohmeyer C, Wolf IA, Cirulli F, Gass P, Sütterlin MW, Filsinger B, Laucht M, Riva MA, Rietschel M, Deuschle M, Szyf M - Transl Psychiatry (2014)

Expanded views from the UCSC genome browser of the MORC1 gene are depicted. (a) Human CD34+ cord blood. (b) 14–30-day-old monkey CD3+ T cells (TC/D14–30), 2-year-old monkey CD3+ T cells (TC/2y). Numbers 1, 2, 3 indicate the locations of DNA amplification for QPCR validations. (c) Rat PFC. For each graph, average methylation probe fold differences (Log2) between control and ELS groups, as well as regions of significant differential methylation are shown. The last track shows the MORC1 gene, as taken from the NCBI reference sequences collection (RefSeq). QPCR analysis of DNA methylation differences in the MORC1 gene between ELS and control groups are displayed. Relative bound fraction concentrations are shown. Error bars represent s.e.m. The symbol ‘*' denotes P-values <0.05, as calculated with the Mann–Whitney U-test. Ctrl, control group; ELS, early life stress; MORC1, MORC family CW-type zinc finger 1; QPCR, quantitative PCR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150246&req=5

fig1: Expanded views from the UCSC genome browser of the MORC1 gene are depicted. (a) Human CD34+ cord blood. (b) 14–30-day-old monkey CD3+ T cells (TC/D14–30), 2-year-old monkey CD3+ T cells (TC/2y). Numbers 1, 2, 3 indicate the locations of DNA amplification for QPCR validations. (c) Rat PFC. For each graph, average methylation probe fold differences (Log2) between control and ELS groups, as well as regions of significant differential methylation are shown. The last track shows the MORC1 gene, as taken from the NCBI reference sequences collection (RefSeq). QPCR analysis of DNA methylation differences in the MORC1 gene between ELS and control groups are displayed. Relative bound fraction concentrations are shown. Error bars represent s.e.m. The symbol ‘*' denotes P-values <0.05, as calculated with the Mann–Whitney U-test. Ctrl, control group; ELS, early life stress; MORC1, MORC family CW-type zinc finger 1; QPCR, quantitative PCR.
Mentions: MDD is one of the well-established ELS-associated phenotypes.1, 2, 3, 4 We therefore took advantage of a previous GWAS study on MDD36 and performed a gene-based case–control analysis to test for an association between genetic variants in those overlapping genes and MDD. We excluded U6 and 7SK from our analysis, as multiple copies of those genes exist throughout the genome. In addition, we had to exclude PRMT5 and PDE4DIP as no genetic variants in PDE4DIP and only one genetic variant in PRMT5 were represented in the quality-controlled GWAS data set. Of the remaining three genes, MORC1 and CSRNP3 showed a nominally significant association with MDD (P=0.00483 and 0.03139, respectively). Only the association of MORC1 with MDD withstood Bonferroni correction for the number of genes tested (P=0.01449), thus providing evidence that MORC1 is involved in MDD, a stress-associated disorder. QPCR was used to validate MORC1 methylation changes observed in human CD34+ cells, monkey CD3+ T cells and rat PFC (Figure 1).

Bottom Line: Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms.MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood.Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany [2] Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany.

ABSTRACT
Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

Show MeSH
Related in: MedlinePlus