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1.
Nat Commun ; 14(1): 7024, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37919291

RESUMO

After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are taking part in fine-tuning such gene programs. We describe and characterize the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function but becomes essential for the tissue adaptation process after myocardial infarction in murine males. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes that depend on Swhtr after cardiac stress are significantly occupied and therefore most likely regulated by NKX2-5. The Swhtr transcript interacts with NKX2-5 and disperses upon hypoxic stress in cardiomyocytes, indicating an auxiliary role of Swhtr for NKX2-5 function in tissue adaptation after myocardial injury.


Assuntos
Traumatismos Cardíacos , Infarto do Miocárdio , RNA Longo não Codificante , Masculino , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Miócitos Cardíacos/metabolismo , Cardiomegalia/genética , Cardiomegalia/metabolismo , Infarto do Miocárdio/metabolismo
2.
Nucleic Acids Res ; 51(12): 6227-6237, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37207329

RESUMO

Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via an RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and found that this FendrrBox is partially required for Fendrr function in vivo. We found that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in lung fibroblasts. We biophysically confirmed the formation of an RNA:dsDNA triplex with target promoters in vitro. We found that Fendrr with the Wnt signalling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signalling in lung fibrosis.


Assuntos
Fibrose Pulmonar , RNA Longo não Codificante , Animais , Camundongos , Fibrose , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/metabolismo
3.
Mech Dev ; 133: 23-35, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25020278

RESUMO

Mesoderm formation in the mouse embryo initiates around E6.5 at the primitive streak and continues until the end of axis extension at E12.5. It requires the process of epithelial-to-mesenchymal transition (EMT), wherein cells detach from the epithelium, adopt mesenchymal cell morphology, and gain competence to migrate. It was shown previously that, prior to mesoderm formation, the transcription factor SRF (Serum Response Factor) is essential for the formation of the primitive streak. To elucidate the role of murine Srf in mesoderm formation during axis extension we conditionally inactivated Srf in nascent mesoderm using the T(s)::Cre driver mouse. Defects in mutant embryos became apparent at E8.75 in the heart and in the allantois. From E9.0 onwards body axis elongation was arrested. Using genome-wide expression analysis, combined with SRF occupancy data from ChIP-seq analysis, we identified a set of direct SRF target genes acting in posterior nascent mesoderm which are enriched for transcripts associated with migratory function. We further show that cell migration is impaired in Srf mutant embryos. Thus, the primary role for SRF in the nascent mesoderm during elongation of the embryonic body axis is the activation of a migratory program, which is a prerequisite for axis extension.


Assuntos
Mesoderma/embriologia , Mesoderma/metabolismo , Fator de Resposta Sérica/metabolismo , Animais , Padronização Corporal/genética , Padronização Corporal/fisiologia , Caderinas/metabolismo , Movimento Celular/genética , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Proteínas Fetais/deficiência , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Adesões Focais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator de Resposta Sérica/deficiência , Fator de Resposta Sérica/genética , Fibras de Estresse/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Vimentina/metabolismo
4.
Dev Cell ; 24(2): 206-14, 2013 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-23369715

RESUMO

The histone-modifying complexes PRC2 and TrxG/MLL play pivotal roles in determining the activation state of genes controlling pluripotency, lineage commitment, and cell differentiation. Long noncoding RNAs (lncRNAs) can bind to either complex, and some have been shown to act as modulators of PRC2 or TrxG/MLL activity. Here we show that the lateral mesoderm-specific lncRNA Fendrr is essential for proper heart and body wall development in the mouse. Embryos lacking Fendrr displayed upregulation of several transcription factors controlling lateral plate or cardiac mesoderm differentiation, accompanied by a drastic reduction in PRC2 occupancy along with decreased H3K27 trimethylation and/or an increase in H3K4 trimethylation at their promoters. Fendrr binds to both the PRC2 and TrxG/MLL complexes, suggesting that it acts as modulator of chromatin signatures that define gene activity. Thus, we identified an lncRNA that plays an essential role in the regulatory networks controlling the fate of lateral mesoderm derivatives.


Assuntos
Desenvolvimento Embrionário , Coração/embriologia , Proteína de Leucina Linfoide-Mieloide/metabolismo , Complexo Repressor Polycomb 2/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Diferenciação Celular/genética , Metilação de DNA , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Camundongos , Dados de Sequência Molecular , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Fatores de Transcrição/metabolismo , Proteína Homeobox PITX2
5.
Eur J Hum Genet ; 18(1): 81-7, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19639020

RESUMO

Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. The phenotype is highly variable, with 'modifiers' being discussed as potential determinants. Mismatch repair deficiency was shown to cause NF1 mutations, but constitutional mutation of mismatch repair genes was identified only once in a NF1 patient. We aimed to analyze whether DNA methylation of mismatch repair gene promoters, known to lead to transcriptional silencing, is associated with increased tumor load in NF1 defined by the number of cutaneous neurofibromas. Leukocyte DNA of 79 controls and 79 NF1 patients was investigated for methylation of mismatch repair genes MLH1, MSH2, MSH6, and PMS2 by methylation-specific PCR and pyrosequencing. MLH1, MSH6, and PMS2 promoters were not methylated. By contrast, we found promoter methylation of MSH2 with a higher rate of methylation in NF1 patients compared with controls. Furthermore, when comparing NF1 patients with a low vs those with a high number of cutaneous neurofibromas, MSH2 promoter methylation was significantly different. In patients with a high tumor burden, methylation of two (out of six) CpGs was enhanced. This finding was not confounded by age. In conclusion, enhanced methylation involving transcription start points of mismatch repair genes, such as MSH2 in NF1, has not been described so far. Methylation-induced variability of MSH2 gene expression may lead to variable mismatch repair capacity. Our results may point toward a role of MSH2 as a modifier for NF1, although the amount of DNA methylation and subsequent gene expression in other cell types of NF1 patients needs to be elucidated.


Assuntos
Células Sanguíneas/metabolismo , Metilação de DNA/genética , Proteína 2 Homóloga a MutS/genética , Neurofibromatose 1/genética , Regiões Promotoras Genéticas , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Ilhas de CpG/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
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