12674
2012
eng
747-762
3
35
article
1
2016-02-05
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--
MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart
MicroRNAs (miRs) are small non- coding RNA molecules controlling a plethora of biological processes such as development, cellular survival and senescence. We here determined miRs differentially regulated during cardiac postnatal development and aging. Cardiac function, morphology and miR expression profiles were determined in neonatal, 4 weeks, 6 months and 19 months old normotensive male healthy C57/Bl6N mice. MiR-22 was most prominently upregulated during cardiac aging. Cardiac expression of its bioinformatically predicted target mimecan (osteoglycin, OGN) was gradually decreased with advanced age. Luciferase reporter assays validated mimecan as a bona fide miR-22 target. Both, miR-22 and its target mimecan were co- expressed in cardiac fibroblasts and smooth muscle cells. Functionally, miR-22 overexpression induced cellular senescence and promoted migratory activity of cardiac fibroblasts. Small interference RNA-mediated silencing of mimecan in cardiac fibroblasts mimicked the miR-22-mediated effects. Rescue experiments revealed that the effects of miR-22 on cardiac fibroblasts were only partially mediated by mimecan. In conclusion, miR-22 upregulation in the aging heart contributed at least partly to accelerated cardiac fibroblast senescence and increased migratory activity. Our results suggest an involvement of miR-22 in age-associated cardiac changes, such as cardiac fibrosis.
AGE
10.1007/s11357-012-9407-9
urn:nbn:de:bvb:20-opus-126745
AGE (2013) 35:747–762 DOI 10.1007/s11357-012-9407-9
Virginija Jazbutyte
Jan Fiedler
Susanne Kneitz
Paolo Galuppo
Annette Just
Angelika Holzmann
Johann Bauersachs
Thomas Thum
eng
uncontrolled
cardiac fibrosis
eng
uncontrolled
cardiac aging
eng
uncontrolled
microRNAs
eng
uncontrolled
miR-22
eng
uncontrolled
mimecan
eng
uncontrolled
osteoglycin
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12674/Jazbutyte_Fs11357-012-9407-9.pdf
6550
2012
eng
article
1
2013-04-15
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Conserved expression signatures between medaka and human pigment cell tumors
Aberrations in gene expression are a hallmark of cancer cells. Differential tumor-specific transcript levels of single genes or whole sets of genes may be critical for the neoplastic phenotype and important for therapeutic considerations or useful as biomarkers. As an approach to filter out such relevant expression differences from the plethora of changes noted in global expression profiling studies, we searched for changes of gene expression levels that are conserved. Transcriptomes from massive parallel sequencing of different types of melanoma from medaka were generated and compared to microarray datasets from zebrafish and human melanoma. This revealed molecular conservation at various levels between fish models and human tumors providing a useful strategy for identifying expression signatures strongly associated with disease phenotypes and uncovering new melanoma molecules.
urn:nbn:de:bvb:20-opus-75848
7584
In: PLoS One (2012) 7: 5, doi:10.1371/journal.pone.0037880
Manfred Schartl
Susanne Kneitz
Brigitta Wilde
Toni Wagner
Christiaan V. Henkel
Hermann P. Spaink
Svenja Meierjohann
deu
swd
Biologie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2012
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6550/052_journal.pone.0037880.pdf
6501
2012
eng
article
1
2013-03-25
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Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors
HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an Ebox motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.
urn:nbn:de:bvb:20-opus-75341
7534
In: PLoS Genetics (2012) 8: 5, doi:10.1371/journal.pgen.1002728
Julia Heisig
David Weber
Eva Englberger
Anja Winkler
Susanne Kneitz
Wing-Kin Sung
Elmar Wolf
Martin Eilers
Chia-Lin Wei
Manfred Gessler
deu
swd
Biologie
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2012
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6501/026_journal.pgen.1002728.pdf