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Series GSE235623 Query DataSets for GSE235623
Status Public on Mar 05, 2024
Title MERTK inhibition for the treatment of tissue fibrosis [RNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Fibrosis is a core pathway that drives the progression of multiple chronic diseases for which there is a paucity of safe and effective treatments. In these diseases, transforming growth factor–β (TGF-β)–driven scarring propels disease progression. However, targeting this ubiquitously expressed cytokine is unlikely to yield a viable and safe antifibrotic therapy; thus, identification of alternative mechanisms to inhibit TGF-β signalling is required. We identified Mer tyrosine kinase (MERTK) as a TGF-β–inducible nodal effector of fibrosis that is up-regulated with fibrosis in multiple organs in both mice and humans. MERTK also induces TGF-β expression and promotes it’s signalling resulting in a positive feedback loop that promotes fibrosis. Mechanistically, MERTK regulates both canonical and non-canonical TGFβ signalling. Further downstream, MERTK modulates the fibrotic regulatory gene transcription network by regulating chromatin accessibility, RNA polymerase II (pol II) pausing and reprograming the enhancer landscape. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrosis-promoting signalling loop can be interrupted by loss of MERTK expression, leading to marked attenuation of fibrosis. Pharmacologic MERTK inhibition reduced fibrosis either when initiated immediately after injury or when initiated after fibrosis is established. Together, this data suggests that MERTK plays a critical role in modulating organ fibrosis, while small-molecule MERTK inhibitors are an attractive target for the treatment of diseases characterized by fibrosis.
Overall design Comparative gene expression profiling analysis of RNA-seq data for WT and Mertk knockout mice liver, kidney tissue of liver, kidney fibrosis models. Comparative gene expression profiling analysis of RNA-seq data for WT and MERTK inhibitor (UNC569) injection mice liver, kidney, and lung tissue of liver, kidney, and lung fibrosis models.
Contributor(s) Pan Z, El Sharkway R, Bayoumi A, Metwally M, Gloss BS, Brink R, Lu DB, Liddle C, Yu J, O'Connell PJ, George J, Eslam M
Citation(s) 38569018
Submission date Jun 22, 2023
Last update date Apr 06, 2024
Contact name Ziyan Pan
Organization name Westmead Institute for Medical Resea
Department Storr Liver Centre
Street address 176 Hawkesbury Rd
City Westmead
State/province NSW
ZIP/Postal code 2145
Country Australia
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (86)
GSM7506324 UUO Sham WT 1
GSM7506325 UUO Sham WT 2
GSM7506326 UUO Sham WT 3
This SubSeries is part of SuperSeries:
GSE235624 MERTK inhibition for the treatment of tissue fibrosis
BioProject PRJNA986572

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE235623_BDL_Replicates_FPKM.txt.gz 1.2 Mb (ftp)(http) TXT
GSE235623_Bleo_Replicates_FPKM.txt.gz 1.5 Mb (ftp)(http) TXT
GSE235623_RAW.tar 6.3 Mb (http)(custom) TAR (of TAB)
GSE235623_UUO_Replicates_FPKM.txt.gz 1.4 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Processed data provided as supplementary file
Processed data are available on Series record
Raw data are available in SRA

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