Circular RNA circPLOD2 regulates pericyte function by targeting the transcription factor KLF4

Glaser, Simone F.; Brezski, Andre; Baumgarten, Nina; Klangwart, Marius; Heumueller, Andreas W.; Maji, Ranjan Kumar; Leisegang, Matthias; Guenther, Stefan; Zehendner, Christoph M.; John, David; Schulz, Marcel H.; Zarnack, Kathi; Dimmeler, Stefanie

doi:10.1101/2022.12.04.519017

Cited by 2 publications

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“…The interaction between pericytes and endothelial cells was assessed using a 3D Matrigel Matrix (#354230, Corning). To allow imaging, the experiment was performed using viral transfected GFP-expressing HBVPs 20,21 , which were subsequently transfected with siRNA as described above, while HUVECs were seeded in medium supplemented with Red-Dil-Ac-LDL (10 µg/mL, L3484, Invitrogen) and incubated overnight at 37°C. In brief, HUVECs were seeded on top of the gel and incubated for 3 hours at 37°C.…”

Section: Pericyte-endothelial Cell Adhesion Assaymentioning

confidence: 99%

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Tamiato,

Tombor,

Fischer

et al. 2023

Preprint

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BackgroundPericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although ageing is one of the main risk factors for cardiovascular disease, the consequences of ageing on cardiac pericytes are unknown.MethodsIn this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of Regulator of G protein signalling 5 (RGS5) loss of function and finally have performed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 deletion in pericytes on the neighbouring fibroblasts.ResultsAgeing reduced the pericyte area and capillary coverage in the murine heart. Single nucleus RNA sequencing analysis further revealed that the expression ofRgs5was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, fibrosis, and induced morphological changes and a pro-fibrotic gene expression signature in pericytes characterized by the expression of different extracellular matrix components and growth factors e.g.TGFB2andPDGFB.Indeed, culturing fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation as evidenced by the increased expression of α smooth muscle actin in a TGFβ2-dependent mechanism.ConclusionsOur results have identified RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.

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Section: Pericyte-endothelial Cell Adhesion Assaymentioning

confidence: 99%

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Tamiato,

Tombor,

Fischer

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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“…The paper Circular RNA circPLOD2 regulates pericyte function by targeting the transcription factor KLF4 is available as preprint on bioRxiv (Glaser et al, 2022). Parts of the following sections include the figures and text to which we contribute in this paper.…”

Section: Application: Circular Rna Circplod2 Regulates Pericyte Funct...mentioning

confidence: 99%

Prediction of transcription factor binding using epigenomics and genome variation data

Baumgarten

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A central concern in genetics is to identify mechanisms of transcriptional regulation. The aim is to unravel the mapping between the DNA sequence and gene expression. However, it turned out that this is extremely complex. Gene regulation is highly cell type-specific and even moderate changes in gene ex- pression can have functional consequences. Important contributors to gene regulation are transcription factors (TFs), that are able to directly interact with the DNA. Often, a first step in understanding the effect of a TF on the gene’s regulation is to identify the genomic regions a TF binds to. Therefore, one needs to be aware of the TF’s binding preferences, which are commonly summarized in TF binding motifs. Although for many TFs the binding motif is experimentally validated, there is still a large number of TFs where no binding motif is known. There exist many tools that link TF binding motifs to TFs. We developed the method Massif that improves the performance of such tools by incorporating a domain score that uses the DNA binding domain of the studied TF as additional information. TF binding sites are often enriched in regulatory elements (REMs) such as promoters or enhancers, where the latter can be located megabases away from its target gene. However, to understand the regulation of a gene it is crucial to know where the REMs of a gene are located. We introduced the EpiRegio webserver that holds REMs associated to target genes predicted across many cell types and tissues using STITCHIT, a previously established method. Our publicly available webserver enables to query for REMs associated to genes (gene query) and REMs overlapping genomic regions (region query). We illus- trated the usefulness of EpiRegio by pointing to a TF that occurs enriched in the REMs of differential expressed genes in circPLOD2 depleted pericytes. Further, we highlighted genes, which are affected by CRISPR-Cas induced mutations in non-coding genomic regions using EpiRegio’s region query. Non-coding genetic variants within REMs may alter gene expression by modifying TF binding sites, which can lead to various kinds of traits or diseases. To understand the underlying molecular mechanisms, one aims to evaluate the effect of such genetic variations on TF binding sites. We developed an accurate and fast statistical approach, that can assess whether a single nucleotide polymorphism (SNP) is regulatory. Further, we combined this approach with epigenetic data and additional analyses in our Sneep workflow. For instance, it enables to identify TFs whose binding preferences are affected by the analyzed SNPs, which is illustrated on eQTL datasets for different cell types. Additionally, we used our Sneep workflow to highlight cardiovascular disease genes using regulatory SNPs and REM-gene interactions. Overall, the described results allow a better understanding of REM-gene interactions and their interplay with TFs on gene regulation.

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Circular RNA circPLOD2 regulates pericyte function by targeting the transcription factor KLF4

Cited by 2 publications

References 51 publications

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Prediction of transcription factor binding using epigenomics and genome variation data

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