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Article ; Online: Involvement of long non-coding RNAs in beta cell failure at the onset of type 1 diabetes in NOD mice.

Motterle, Anna / Gattesco, Sonia / Caille, Dorothée / Meda, Paolo / Regazzi, Romano

2015 Volume 58, Issue 8, Page(s) 1827–1835

Abstract: Aims/hypothesis: Exposure of pancreatic beta cells to cytokines released by islet-infiltrating immune cells induces alterations in gene expression, leading to impaired insulin secretion and apoptosis in the initial phases of type 1 diabetes. Long non- ... ...

Abstract	Aims/hypothesis: Exposure of pancreatic beta cells to cytokines released by islet-infiltrating immune cells induces alterations in gene expression, leading to impaired insulin secretion and apoptosis in the initial phases of type 1 diabetes. Long non-coding RNAs (lncRNAs) are a new class of transcripts participating in the development of many diseases. As little is known about their role in insulin-secreting cells, this study aimed to evaluate their contribution to beta cell dysfunction. Methods: The expression of lncRNAs was determined by microarray in the MIN6 beta cell line exposed to proinflammatory cytokines. The changes induced by cytokines were further assessed by real-time PCR in islets of control and NOD mice. The involvement of selected lncRNAs modified by cytokines was assessed after their overexpression in MIN6 cells and primary islet cells. Results: MIN6 cells were found to express a large number of lncRNAs, many of which were modified by cytokine treatment. The changes in the level of selected lncRNAs were confirmed in mouse islets and an increase in these lncRNAs was also seen in prediabetic NOD mice. Overexpression of these lncRNAs in MIN6 and mouse islet cells, either alone or in combination with cytokines, favoured beta cell apoptosis without affecting insulin production or secretion. Furthermore, overexpression of lncRNA-1 promoted nuclear translocation of nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB). Conclusions/interpretation: Our study shows that lncRNAs are modulated during the development of type 1 diabetes in NOD mice, and that their overexpression sensitises beta cells to apoptosis, probably contributing to their failure during the initial phases of the disease.
MeSH term(s)	Animals ; Cell Line ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Disease Progression ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Islets of Langerhans/metabolism ; Islets of Langerhans/pathology ; Mice ; Mice, Inbred NOD ; Prediabetic State/metabolism ; Prediabetic State/pathology ; RNA, Long Noncoding
Chemical Substances	Insulin ; RNA, Long Noncoding
Language	English
Publishing date	2015-08
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-015-3641-5
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Article ; Online: Common variant on chromosome 9p21 predicts severity of coronary artery disease.

Chan, Kenneth / Motterle, Anna / Laxton, Ross C / Ye, Shu

Journal of the American College of Cardiology

2011 Volume 57, Issue 13, Page(s) 1497–8; author reply 1498–9

MeSH term(s)	Alleles ; Chromosomes, Human, Pair 9/genetics ; Cohort Studies ; Coronary Artery Disease/epidemiology ; Coronary Artery Disease/genetics ; Coronary Stenosis/epidemiology ; Diabetes Mellitus/epidemiology ; Genetic Predisposition to Disease ; Humans ; Logistic Models ; Middle Aged ; Polymorphism, Single Nucleotide ; Severity of Illness Index
Language	English
Publishing date	2011-03-29
Publishing country	United States
Document type	Comment ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2010.09.078
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Article ; Online: Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes.

Motterle, Anna / Gattesco, Sonia / Peyot, Marie-Line / Esguerra, Jonathan Lou S / Gomez-Ruiz, Ana / Laybutt, D Ross / Gilon, Patrick / Burdet, Frédéric / Ibberson, Mark / Eliasson, Lena / Prentki, Marc / Regazzi, Romano

Molecular metabolism

2017 Volume 6, Issue 11, Page(s) 1407–1418

Abstract: Objective: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-cell functions and in diabetes ... ...

Abstract	Objective: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-cell functions and in diabetes development remains poorly understood. The aim of this study was to identify novel islet lncRNAs differently expressed in type 2 diabetes models and to investigate their role in β-cell failure and in the development of the disease. Methods: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified by high throughput RNA-sequencing coupled with de novo annotation. Changes in the level of the lncRNAs were assessed by real-time PCR. The functional role of the selected lncRNAs was determined by modifying their expression in MIN6 cells and primary islet cells. Results: We identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in β-cells, βlinc2, and βlinc3, correlated to body weight gain and glycemia levels in obese mice and was also modified in diabetic db/db mice. The expression of both lncRNAs was also modulated in vitro in isolated islet cells by glucolipotoxic conditions. Moreover, the expression of the human orthologue of βlinc3 was altered in the islets of type 2 diabetic patients and was associated to the BMI of the donors. Modulation of the level of βlinc2 and βlinc3 by overexpression or downregulation in MIN6 and mouse islet cells did not affect insulin secretion but increased β-cell apoptosis. Conclusions: Taken together, the data show that lncRNAs are modulated in a model of obesity-associated type 2 diabetes and that variations in the expression of some of them may contribute to β-cell failure during the development of the disease.
MeSH term(s)	Animals ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat ; Disease Models, Animal ; Gene Expression/genetics ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Sequence Analysis, RNA ; Transcriptome
Chemical Substances	Insulin ; RNA, Long Noncoding
Language	English
Publishing date	2017-08-18
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2017.08.005
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Article ; Online: Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes

Anna Motterle / Sonia Gattesco / Marie-Line Peyot / Jonathan Lou S. Esguerra / Ana Gomez-Ruiz / D. Ross Laybutt / Patrick Gilon / Frédéric Burdet / Mark Ibberson / Lena Eliasson / Marc Prentki / Romano Regazzi

Molecular Metabolism, Vol 6, Iss 11, Pp 1407-

2017 Volume 1418

Abstract	Objective: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-cell functions and in diabetes development remains poorly understood. The aim of this study was to identify novel islet lncRNAs differently expressed in type 2 diabetes models and to investigate their role in β-cell failure and in the development of the disease. Methods: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified by high throughput RNA-sequencing coupled with de novo annotation. Changes in the level of the lncRNAs were assessed by real-time PCR. The functional role of the selected lncRNAs was determined by modifying their expression in MIN6 cells and primary islet cells. Results: We identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in β-cells, βlinc2, and βlinc3, correlated to body weight gain and glycemia levels in obese mice and was also modified in diabetic db/db mice. The expression of both lncRNAs was also modulated in vitro in isolated islet cells by glucolipotoxic conditions. Moreover, the expression of the human orthologue of βlinc3 was altered in the islets of type 2 diabetic patients and was associated to the BMI of the donors. Modulation of the level of βlinc2 and βlinc3 by overexpression or downregulation in MIN6 and mouse islet cells did not affect insulin secretion but increased β-cell apoptosis. Conclusions: Taken together, the data show that lncRNAs are modulated in a model of obesity-associated type 2 diabetes and that variations in the expression of some of them may contribute to β-cell failure during the development of the disease.
Keywords	Diabetes ; Insulin ; Pancreatic islet ; Obesity ; Gene expression ; Internal medicine ; RC31-1245
Subject code	571
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Influence of matrix metalloproteinase-12 on fibrinogen level.

Motterle, Anna / Xiao, Qingzhong / Kiechl, Stefan / Pender, Sylvia L F / Morris, Gareth E / Willeit, Johann / Caulfield, Mark J / Ye, Shu

Atherosclerosis

2011 Volume 220, Issue 2, Page(s) 351–354

Abstract: In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was ... ...

Abstract	In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was approximately 10-fold higher in MMP12 knockout mice than wildtype mice (p=0.0006). Differential allelic expression analysis of human MMP12 gene polymorphism rs17368582 in human vascular tissues showed an allele-specific effect on MMP12 expression, with one allele (T) having 1.6 fold higher expression level than the other allele (C) (p=0.0006). In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95 mg/mL compared with 2.61 mg/mL in other individuals, p=0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9-20.8), p=0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7-18.3), p=0.005]. In summary, our study in mouse and humans provides in vivo evidence of an effect of MMP12 on fibrinogen level.
MeSH term(s)	Animals ; Atherosclerosis/enzymology ; Atherosclerosis/genetics ; England ; Fibrinogen/metabolism ; Gene Frequency ; Genetic Predisposition to Disease ; Homozygote ; Humans ; Italy ; Linear Models ; Linkage Disequilibrium ; Logistic Models ; Matrix Metalloproteinase 12/deficiency ; Matrix Metalloproteinase 12/genetics ; Matrix Metalloproteinase 12/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial Infarction/enzymology ; Myocardial Infarction/genetics ; Odds Ratio ; Phenotype ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Prospective Studies ; Risk Assessment ; Risk Factors
Chemical Substances	Fibrinogen (9001-32-5) ; MMP12 protein, human (EC 3.4.24.65) ; Matrix Metalloproteinase 12 (EC 3.4.24.65)
Language	English
Publishing date	2011-11-11
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2011.11.003
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Article: Influence of matrix metalloproteinase-12 on fibrinogen level

Motterle, Anna / Xiao, Qingzhong / Kiechl, Stefan / Pender, Sylvia L.F / Morris, Gareth E / Willeit, Johann / Caulfield, Mark J / Ye, Shu

Atherosclerosis. 2012 Feb., v. 220, no. 2

2012

Abstract	In vitro studies have shown that matrix metalloproteinase-12 (MMP12) can degrade fibrinogen, a clotting factor whose level predicts risk of advanced atherosclerosis and myocardial infarction. In this study, we found that mean plasma fibrinogen level was approximately 10-fold higher in MMP12 knockout mice than wildtype mice (p=0.0006). Differential allelic expression analysis of human MMP12 gene polymorphism rs17368582 in human vascular tissues showed an allele-specific effect on MMP12 expression, with one allele (T) having 1.6 fold higher expression level than the other allele (C) (p=0.0006). In a population cohort, we found that individuals homozygous for the MMP12 low expression allele had higher plasma fibrinogen levels (2.95mg/mL compared with 2.61mg/mL in other individuals, p=0.029) and increased risk of advanced atherosclerosis [odds ratio 6.3 (95% CI 1.9–20.8), p=0.003] and myocardial infarction [hazard ratio 5.6 (95% CI 1.7–18.3), p=0.005]. In summary, our study in mouse and humans provides in vivo evidence of an effect of MMP12 on fibrinogen level.
Keywords	alleles ; atherosclerosis ; fibrinogen ; genetic polymorphism ; homozygosity ; humans ; in vitro studies ; mice ; myocardial infarction ; odds ratio ; risk ; vascular tissues
Language	English
Dates of publication	2012-02
Size	p. 351-354.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2011.11.003
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Article ; Online: Single nucleotide polymorphism on chromosome 9p21 and endothelial progenitor cells in a general population cohort.

Ye, Shu / Willeit, Johann / Xiao, Qingzhong / Motterle, Anna / Laxton, Ross C / Oberhollenzer, Friedrich / Kiechl, Stefan / Xu, Qingbo

Atherosclerosis

2009 Volume 208, Issue 2, Page(s) 451–455

Abstract: Objective: Recent studies have revealed that sequence variation on chromosome 9p21 is a major genetic determinant for coronary heart disease and stroke, however, the underlying mechanism remains unknown. This genomic region contains the gene encoding ... ...

Abstract	Objective: Recent studies have revealed that sequence variation on chromosome 9p21 is a major genetic determinant for coronary heart disease and stroke, however, the underlying mechanism remains unknown. This genomic region contains the gene encoding cyclin-dependent kinase 2A, a regulator of proliferation and differentiation of endothelial progenitor cell (EPC) which has been implicated in vascular repair and protection against cardiovascular disease. We investigated whether carriers and non-carriers of the chromosome 9p21 variation differed in their number and function of EPCs. Methods: We genotyped a cohort of 769 individuals (who participated in the Bruneck Study) for the single nucleotide polymorphism rs1333049 on chromosome 9p21 and determined circulating EPC numbers and EPC colony formation units (n=538 and 512, respectively). Results: There was no evidence of reduced EPC numbers or colony formation units in carriers of the chromosome 9p21 risk variant. On the contrary, circulating EPC numbers and colony formation units tended to be higher in carriers of the variant (p=0.189 for EPC numbers and p=0.190 for EPC colony formation units). Conclusion: These results indicate that the chromosome 9p21 variant does not influence the risk of coronary heart disease and stroke through an effect on circulating EPCs.
MeSH term(s)	Adult ; Aged ; Cardiovascular Diseases/genetics ; Cell Proliferation ; Chromosomes, Human, Pair 9 ; Cohort Studies ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Endothelial Cells/cytology ; Female ; Gene Expression Regulation ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Risk ; Stem Cells/cytology
Chemical Substances	Cyclin-Dependent Kinase Inhibitor p16
Language	English
Publishing date	2009-08-08
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2009.08.006
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Article ; Online: Cardiac expression of ms1/STARS, a novel gene involved in cardiac development and disease, is regulated by GATA4.

Ounzain, Samir / Kobayashi, Satoru / Peterson, Richard E / He, Aibin / Motterle, Anna / Samani, Nilesh J / Menick, Donald R / Pu, William T / Liang, Qiangrong / Chong, Nelson W

Molecular and cellular biology

2012 Volume 32, Issue 10, Page(s) 1830–1843

Abstract: Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of ... ...

Abstract	Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease.
MeSH term(s)	Animals ; Cell Line ; GATA4 Transcription Factor/metabolism ; Gene Expression Regulation ; Heart/embryology ; Heart Diseases/genetics ; Heart Diseases/metabolism ; Mice ; Mice, Transgenic ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Myocardium/metabolism ; Rats ; Regulatory Sequences, Nucleic Acid ; Serum Response Factor/metabolism ; Signal Transduction ; Trans-Activators/metabolism
Chemical Substances	Abra protein, mouse ; GATA4 Transcription Factor ; Gata4 protein, mouse ; Microfilament Proteins ; Mrtfa protein, mouse ; Serum Response Factor ; Trans-Activators
Language	English
Publishing date	2012-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.06374-11
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Article ; Online: Functional analyses of coronary artery disease associated variation on chromosome 9p21 in vascular smooth muscle cells.

Motterle, Anna / Pu, Xiangyuan / Wood, Harriet / Xiao, Qingzhong / Gor, Shivani / Ng, Fu Liang / Chan, Kenneth / Cross, Frank / Shohreh, Beski / Poston, Robin N / Tucker, Arthur T / Caulfield, Mark J / Ye, Shu

Human molecular genetics

2012 Volume 21, Issue 18, Page(s) 4021–4029

Abstract: Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a ... ...

Abstract	Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 × 10(-5), 1.4 × 10(-2) and 3.1 × 10(-9)) and with increased VSMC proliferation (P = 1.6 × 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 × 10(-2)) and higher VSMC content (P = 5.6 × 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD.
MeSH term(s)	Atherosclerosis/genetics ; Atherosclerosis/metabolism ; Atherosclerosis/pathology ; Cell Proliferation ; Cells, Cultured ; Chromosomes, Human, Pair 9/genetics ; Coronary Artery Disease/genetics ; Coronary Artery Disease/metabolism ; Coronary Artery Disease/pathology ; Cyclin-Dependent Kinase Inhibitor p15/genetics ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Gene Expression ; Genetic Association Studies ; Genotype ; Humans ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/physiology ; Plaque, Atherosclerotic/genetics ; Plaque, Atherosclerotic/metabolism ; Polymorphism, Single Nucleotide ; Primary Cell Culture ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
Chemical Substances	CDKN2B antisense RNA, human ; CDKN2B protein, human ; Cyclin-Dependent Kinase Inhibitor p15 ; Cyclin-Dependent Kinase Inhibitor p16 ; RNA, Long Noncoding
Language	English
Publishing date	2012-06-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/dds224
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Article ; Online: Cardiac Expression of ms1/STARS, a Novel Gene Involved in Cardiac Development and Disease, Is Regulated by GATA4

Ounzain, Samir / Kobayashi, Satoru / Peterson, Richard E. / He, Aibin / Motterle, Anna / Samani, Nilesh J. / Menick, Donald R. / Pu, William T. / Liang, Qiangrong / Chong, Nelson W.

Molecular and Cellular Biology. 2012 May 1, v. 32, no. 10 p.1830-1843

2012

Abstract	Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease.
Keywords	GATA transcription factors ; adults ; cardiac output ; cardiomyopathy ; cell biology ; computer simulation ; gain-of-function mutation ; gene regulatory networks ; genes ; genomics ; heart ; homeostasis ; hypertrophy ; loss-of-function mutation ; microfilament proteins ; striated muscle
Language	English
Dates of publication	2012-0501
Size	p. 1830-1843.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.06374-11
Database	NAL-Catalogue (AGRICOLA)

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In stock of ZB MED Cologne/Königswinter

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito