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Identification of New SRF Binding Sites in Genes Modulated by SRF Over-Expression in Mouse Hearts.

Zhang X, Azhar G, Helms S, Burton B, Huang C, Zhong Y, Gu X, Fang H, Tong W, Wei JY - Gene Regul Syst Bio (2011)

Bottom Line: The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased.Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting cardiac structure and performance.The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart.

View Article: PubMed Central - PubMed

Affiliation: Donald W. Reynolds Department of Geriatrics, The University of Arkansas for Medical Sciences and Geriatric Research, Education, and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.

ABSTRACT

Background: To identify in vivo new cardiac binding sites of serum response factor (SRF) in genes and to study the response of these genes to mild over-expression of SRF, we employed a cardiac-specific, transgenic mouse model, with mild over-expression of SRF (Mild-O SRF Tg).

Methodology: Microarray experiments were performed on hearts of Mild-O-SRF Tg at 6 months of age. We identified 207 genes that are important for cardiac function that were differentially expressed in vivo. Among them the promoter region of 192 genes had SRF binding motifs, the classic CArG or CArG-like (CArG-L) elements. Fifty-one of the 56 genes with classic SRF binding sites had not been previously reported. These SRF-modulated genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased. Using public databases of mouse models of hemodynamic stress (GEO database), we also found that similar altered expression of the SRF-modulated genes occurred in these hearts with cardiac ischemia or aortic constriction as well.

Conclusion and significance: SRF-modulated genes are actively regulated under various physiological and pathological conditions. We have discovered that a large number of cardiac genes have classic SRF binding sites and were significantly modulated in the Mild-O-SRF Tg mouse hearts. Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting cardiac structure and performance. The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart.

No MeSH data available.


Related in: MedlinePlus

Normalized distribution curves of SRF-modulated genes in response to mild-SRF overexpression in vivo. The legend at the top right shows the functional categories as variables. The legend at the bottom right, shows the mean fold change in gene expression, the standard deviation (SD) and the number (N) of genes in each category.
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f4-grsb-5-2011-041: Normalized distribution curves of SRF-modulated genes in response to mild-SRF overexpression in vivo. The legend at the top right shows the functional categories as variables. The legend at the bottom right, shows the mean fold change in gene expression, the standard deviation (SD) and the number (N) of genes in each category.

Mentions: To assess the significance of altered expression of SRF-modulated genes on cardiac function, the 207 SRF-modulated genes were grouped into 12 categories according to their function and Gene Ontology (GO) term. They are energy metabolism, xenobiotic metabolism, cytoskeleton, transcription and translation regulation, extracellular matrix (ECM), stress response, signaling proteins, protease and protease inhibitors, complement and coagulation, ion transport, immune response as well as other proteins (Table 2, Figs. 2, 3 and 4). The 192 genes that contain CArG and/or CArG-like elements were distributed among all of the 12 categories (Table 2). The 56 genes that contain at least one classic CArG element were also found in 11 of the 12 categories (Table 2). Mild over-expression of SRF down-regulated a majority of the genes in 10 categories, but up-regulated most of the genes in the category of cytoskeleton and cellular function (Table S1).


Identification of New SRF Binding Sites in Genes Modulated by SRF Over-Expression in Mouse Hearts.

Zhang X, Azhar G, Helms S, Burton B, Huang C, Zhong Y, Gu X, Fang H, Tong W, Wei JY - Gene Regul Syst Bio (2011)

Normalized distribution curves of SRF-modulated genes in response to mild-SRF overexpression in vivo. The legend at the top right shows the functional categories as variables. The legend at the bottom right, shows the mean fold change in gene expression, the standard deviation (SD) and the number (N) of genes in each category.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140411&req=5

f4-grsb-5-2011-041: Normalized distribution curves of SRF-modulated genes in response to mild-SRF overexpression in vivo. The legend at the top right shows the functional categories as variables. The legend at the bottom right, shows the mean fold change in gene expression, the standard deviation (SD) and the number (N) of genes in each category.
Mentions: To assess the significance of altered expression of SRF-modulated genes on cardiac function, the 207 SRF-modulated genes were grouped into 12 categories according to their function and Gene Ontology (GO) term. They are energy metabolism, xenobiotic metabolism, cytoskeleton, transcription and translation regulation, extracellular matrix (ECM), stress response, signaling proteins, protease and protease inhibitors, complement and coagulation, ion transport, immune response as well as other proteins (Table 2, Figs. 2, 3 and 4). The 192 genes that contain CArG and/or CArG-like elements were distributed among all of the 12 categories (Table 2). The 56 genes that contain at least one classic CArG element were also found in 11 of the 12 categories (Table 2). Mild over-expression of SRF down-regulated a majority of the genes in 10 categories, but up-regulated most of the genes in the category of cytoskeleton and cellular function (Table S1).

Bottom Line: The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased.Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting cardiac structure and performance.The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart.

View Article: PubMed Central - PubMed

Affiliation: Donald W. Reynolds Department of Geriatrics, The University of Arkansas for Medical Sciences and Geriatric Research, Education, and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.

ABSTRACT

Background: To identify in vivo new cardiac binding sites of serum response factor (SRF) in genes and to study the response of these genes to mild over-expression of SRF, we employed a cardiac-specific, transgenic mouse model, with mild over-expression of SRF (Mild-O SRF Tg).

Methodology: Microarray experiments were performed on hearts of Mild-O-SRF Tg at 6 months of age. We identified 207 genes that are important for cardiac function that were differentially expressed in vivo. Among them the promoter region of 192 genes had SRF binding motifs, the classic CArG or CArG-like (CArG-L) elements. Fifty-one of the 56 genes with classic SRF binding sites had not been previously reported. These SRF-modulated genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased. Using public databases of mouse models of hemodynamic stress (GEO database), we also found that similar altered expression of the SRF-modulated genes occurred in these hearts with cardiac ischemia or aortic constriction as well.

Conclusion and significance: SRF-modulated genes are actively regulated under various physiological and pathological conditions. We have discovered that a large number of cardiac genes have classic SRF binding sites and were significantly modulated in the Mild-O-SRF Tg mouse hearts. Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting cardiac structure and performance. The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart.

No MeSH data available.


Related in: MedlinePlus