Two main skeletal muscle molecular phenotypes of mouse dm1 models: a comparative transcriptomic analysis
Authors
Lazić, DušanJovanović, Vladimir
Karanović, Jelena
Savić-Pavićević, Dušanka
Jovanović, Bogdan
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Introduction:Myotonic dystrophy type 1 (DM1) is a rare, incurable multisystemic disease, with the main
symptoms being skeletal muscle weakness, atrophy, and myotonia. It is caused by CTG expansion in the
3' UTR of the DMPK gene whose RNA acquires toxic functions and sequesters MBNL proteins, resulting
in globally altered RNA metabolism. To better understand the DM1 transcriptome, we systematically analyzed
gene expression in the skeletal muscles of various mouse DM1 models.
Methods:We retrieved 13 publicly available RNA-seq datasets from mouse models expressing expanded
CTG repeats (HSALR, CTG480KI, TREDT960I) and Mbnl knockout models (SKO, DKO, TKO). Our bioinformatic
pipeline with unified parameters consisted of preprocessing, differential expression (DESeq2),
gene network analysis (WGCNA), comparison of gene network interactions with the STRING database,
and network node enrichment analysis (Cytoscape).
Results: In models expressing CTG repeats, the average number of up-re...gulated genes was 787, compared
to 676 in Mbnl knockout models, while there was 642 and 380 down-regulated genes, respectively
(log2FC>1, padj>0.05). Both model groups had network modules whose nodes were enriched for muscle
and secretory functions (FDR<0.05). There were modules related to immune response, lipid transfer,
and insulin in models expressing repeats and modules related to immunoglobulins and extracellular
matrix in knockout models.
Conclusion: Gene expression patterns separated Mbnl knockouts from models expressing CTG repeats
that had a greater number of smaller functionally distinct network modules. Our results revealed novel
pathway changes in DM1 skeletal muscles, among which immunological and secretory are particularly
interesting as molecular targets for further investigation.
Keywords:
Myotonic dystrophy type 1 / comparative transcriptomics / DM1 mouse models / gene co-expression networksSource:
CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia, 2023, 67-67Publisher:
- Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
Funding / projects:
- READ-DM1 - Understanding repeat expansion dynamics and phenotype variability in myotonic dystrophy type 1 through human studies, nanopore sequencing and cell models (RS-ScienceFundRS-Ideje-7754217)
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Lazić, Dušan AU - Jovanović, Vladimir AU - Karanović, Jelena AU - Savić-Pavićević, Dušanka AU - Jovanović, Bogdan PY - 2023 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2198 AB - Introduction:Myotonic dystrophy type 1 (DM1) is a rare, incurable multisystemic disease, with the main symptoms being skeletal muscle weakness, atrophy, and myotonia. It is caused by CTG expansion in the 3' UTR of the DMPK gene whose RNA acquires toxic functions and sequesters MBNL proteins, resulting in globally altered RNA metabolism. To better understand the DM1 transcriptome, we systematically analyzed gene expression in the skeletal muscles of various mouse DM1 models. Methods:We retrieved 13 publicly available RNA-seq datasets from mouse models expressing expanded CTG repeats (HSALR, CTG480KI, TREDT960I) and Mbnl knockout models (SKO, DKO, TKO). Our bioinformatic pipeline with unified parameters consisted of preprocessing, differential expression (DESeq2), gene network analysis (WGCNA), comparison of gene network interactions with the STRING database, and network node enrichment analysis (Cytoscape). Results: In models expressing CTG repeats, the average number of up-regulated genes was 787, compared to 676 in Mbnl knockout models, while there was 642 and 380 down-regulated genes, respectively (log2FC>1, padj>0.05). Both model groups had network modules whose nodes were enriched for muscle and secretory functions (FDR<0.05). There were modules related to immune response, lipid transfer, and insulin in models expressing repeats and modules related to immunoglobulins and extracellular matrix in knockout models. Conclusion: Gene expression patterns separated Mbnl knockouts from models expressing CTG repeats that had a greater number of smaller functionally distinct network modules. Our results revealed novel pathway changes in DM1 skeletal muscles, among which immunological and secretory are particularly interesting as molecular targets for further investigation. PB - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade C3 - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia T1 - Two main skeletal muscle molecular phenotypes of mouse dm1 models: a comparative transcriptomic analysis EP - 67 SP - 67 UR - https://hdl.handle.net/21.15107/rcub_imagine_2198 ER -
@conference{ author = "Lazić, Dušan and Jovanović, Vladimir and Karanović, Jelena and Savić-Pavićević, Dušanka and Jovanović, Bogdan", year = "2023", abstract = "Introduction:Myotonic dystrophy type 1 (DM1) is a rare, incurable multisystemic disease, with the main symptoms being skeletal muscle weakness, atrophy, and myotonia. It is caused by CTG expansion in the 3' UTR of the DMPK gene whose RNA acquires toxic functions and sequesters MBNL proteins, resulting in globally altered RNA metabolism. To better understand the DM1 transcriptome, we systematically analyzed gene expression in the skeletal muscles of various mouse DM1 models. Methods:We retrieved 13 publicly available RNA-seq datasets from mouse models expressing expanded CTG repeats (HSALR, CTG480KI, TREDT960I) and Mbnl knockout models (SKO, DKO, TKO). Our bioinformatic pipeline with unified parameters consisted of preprocessing, differential expression (DESeq2), gene network analysis (WGCNA), comparison of gene network interactions with the STRING database, and network node enrichment analysis (Cytoscape). Results: In models expressing CTG repeats, the average number of up-regulated genes was 787, compared to 676 in Mbnl knockout models, while there was 642 and 380 down-regulated genes, respectively (log2FC>1, padj>0.05). Both model groups had network modules whose nodes were enriched for muscle and secretory functions (FDR<0.05). There were modules related to immune response, lipid transfer, and insulin in models expressing repeats and modules related to immunoglobulins and extracellular matrix in knockout models. Conclusion: Gene expression patterns separated Mbnl knockouts from models expressing CTG repeats that had a greater number of smaller functionally distinct network modules. Our results revealed novel pathway changes in DM1 skeletal muscles, among which immunological and secretory are particularly interesting as molecular targets for further investigation.", publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade", journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia", title = "Two main skeletal muscle molecular phenotypes of mouse dm1 models: a comparative transcriptomic analysis", pages = "67-67", url = "https://hdl.handle.net/21.15107/rcub_imagine_2198" }
Lazić, D., Jovanović, V., Karanović, J., Savić-Pavićević, D.,& Jovanović, B.. (2023). Two main skeletal muscle molecular phenotypes of mouse dm1 models: a comparative transcriptomic analysis. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 67-67. https://hdl.handle.net/21.15107/rcub_imagine_2198
Lazić D, Jovanović V, Karanović J, Savić-Pavićević D, Jovanović B. Two main skeletal muscle molecular phenotypes of mouse dm1 models: a comparative transcriptomic analysis. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:67-67. https://hdl.handle.net/21.15107/rcub_imagine_2198 .
Lazić, Dušan, Jovanović, Vladimir, Karanović, Jelena, Savić-Pavićević, Dušanka, Jovanović, Bogdan, "Two main skeletal muscle molecular phenotypes of mouse dm1 models: a comparative transcriptomic analysis" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):67-67, https://hdl.handle.net/21.15107/rcub_imagine_2198 .