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Series GSE131111 Query DataSets for GSE131111
Status Public on Oct 03, 2019
Title Translational control of cardiac fibrosis (II)
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Other
Summary Background: Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. Methods: Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used a RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these post-transcriptional mechanisms are also active in the diseased fibrotic human heart. Results: We generated nucleotide-resolution translatome data during the TGFβ1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same post-transcriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward pro-fibrotic myofibroblasts in response to TGFβ1. Conclusions: We reveal widespread translational effects of TGFβ1 and define novel post-transcriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.
 
Overall design Ribosome profiling of left ventricle tissue of 30 end-stage DCM patients
 
Contributor(s) Chothani S, Schafer S, Adami E, Cook S, Rackham O
Citation(s) 31284728
Submission date May 13, 2019
Last update date Oct 03, 2019
Contact name Sonia Chothani
E-mail(s) [email protected]
Organization name Duke-NUS school of medicine
Lab Prof. Stuart Cook
Street address 8 College Road
City Singapore
ZIP/Postal code 169857
Country Singapore
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (30)
GSM3763596 Left ventricle tissue of end-stage DCM patients (20AP01457)
GSM3763597 Left ventricle tissue of end-stage DCM patients (20CM01195)
GSM3763598 Left ventricle tissue of end-stage DCM patients (20CP01865)
This SubSeries is part of SuperSeries:
GSE131112 Translational control of cardiac fibrosis
Relations
BioProject PRJNA542670
SRA SRP198270

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Supplementary file Size Download File type/resource
GSE131111_Riboseq.counts.txt.gz 3.1 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record
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