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Systematic analysis of gene expression differences between left and right atria in different mouse strains and in human atrial tissue.

Kahr PC, Piccini I, Fabritz L, Greber B, Schöler H, Scheld HH, Hoffmeier A, Brown NA, Kirchhof P - PLoS ONE (2011)

Bottom Line: Normal development of the atria requires left-right differentiation during embryonic development.These differences were validated by RT-qPCR in murine and human tissue.Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany.

ABSTRACT

Background: Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria.

Methods: We compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery.

Results: We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFβ family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c(+/-) atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c.

Conclusions: Our study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining "leftness" in the atrium in adult murine and human hearts.

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Related in: MedlinePlus

Gene groups enriched in left atrium according to FatiGO gene ontology analysis.220 genes significantly enriched in the left atrium in any of the three microarray datasets (MF1_3; MF1_12; SA_12) were used as input list against the genome. 9 biological process, 10 cellular component, and 8 molecular function enriched GO classes are highlighted in red (levels 3–9; P<0.01).
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pone-0026389-g002: Gene groups enriched in left atrium according to FatiGO gene ontology analysis.220 genes significantly enriched in the left atrium in any of the three microarray datasets (MF1_3; MF1_12; SA_12) were used as input list against the genome. 9 biological process, 10 cellular component, and 8 molecular function enriched GO classes are highlighted in red (levels 3–9; P<0.01).

Mentions: To further evaluate how the preferential expression pattern in the left atrium might affect left atrial function, we performed Gene Ontology analysis using FatiGO. All 220 genes enriched in left atrium by array analysis were recognized by the software that could assign GO-biological process terms to 146 genes, GO-cellular component terms to 115, and GO-molecular function to 155. Using the significantly enriched genes in left atrium as input list, 9 GO-biological process terms (levels 3–9), 10 GO-cellular component terms, and 8 GO-molecular function terms were significantly enriched (P<0.01, Figure 2, for a complete list of GO terms see Supplementary Table S3).


Systematic analysis of gene expression differences between left and right atria in different mouse strains and in human atrial tissue.

Kahr PC, Piccini I, Fabritz L, Greber B, Schöler H, Scheld HH, Hoffmeier A, Brown NA, Kirchhof P - PLoS ONE (2011)

Gene groups enriched in left atrium according to FatiGO gene ontology analysis.220 genes significantly enriched in the left atrium in any of the three microarray datasets (MF1_3; MF1_12; SA_12) were used as input list against the genome. 9 biological process, 10 cellular component, and 8 molecular function enriched GO classes are highlighted in red (levels 3–9; P<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198471&req=5

pone-0026389-g002: Gene groups enriched in left atrium according to FatiGO gene ontology analysis.220 genes significantly enriched in the left atrium in any of the three microarray datasets (MF1_3; MF1_12; SA_12) were used as input list against the genome. 9 biological process, 10 cellular component, and 8 molecular function enriched GO classes are highlighted in red (levels 3–9; P<0.01).
Mentions: To further evaluate how the preferential expression pattern in the left atrium might affect left atrial function, we performed Gene Ontology analysis using FatiGO. All 220 genes enriched in left atrium by array analysis were recognized by the software that could assign GO-biological process terms to 146 genes, GO-cellular component terms to 115, and GO-molecular function to 155. Using the significantly enriched genes in left atrium as input list, 9 GO-biological process terms (levels 3–9), 10 GO-cellular component terms, and 8 GO-molecular function terms were significantly enriched (P<0.01, Figure 2, for a complete list of GO terms see Supplementary Table S3).

Bottom Line: Normal development of the atria requires left-right differentiation during embryonic development.These differences were validated by RT-qPCR in murine and human tissue.Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany.

ABSTRACT

Background: Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria.

Methods: We compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery.

Results: We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFβ family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c(+/-) atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c.

Conclusions: Our study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining "leftness" in the atrium in adult murine and human hearts.

Show MeSH
Related in: MedlinePlus