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| Status |
Public on Dec 31, 2020 |
| Title |
RNA-seq: Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation |
| Organism |
Caenorhabditis elegans |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Point mutations in nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery Dreifuss Muscular Dystrophy (EDMD)-inducing mutation (lamin A-Y45C) into C. elegans lamin (LMN-Y59C), recapitulates many EDMD phenotypes, and correlates with hyper-sequestration of heterochromatic arrays at the nuclear periphery. Using muscle-specific emerin Dam-ID, we also document the misorganization of endogenous chromatin in the LMN-Y59C mutant. We score increased perinuclear positioning along chromosome arms, and enhanced release within chromosomal cores. Coincidentally, Y59C worms have reduced locomotion and compromised sarcomere integrity. By coupling the Y59C mutation with deletion of the perinuclear chromodomain protein CEC-4, which tethers H3K9-methylated chromatin, we rescue the EDMD-like physiology and ultrastructural defects in sarcomeres. Deletion of cec-4 also rescued the Y59C-induced changes in chromatin organization. The promoters of genes that change position in the LMN-Y59C mutant, are enriched for E2F (EFL-1/-2) binding sites, consistent with previous studies implicating the Rb-E2F interaction with lamin A in muscle dysfunction. Gene expression changes provoked by LMN-Y59C are also largely reversed by cec-4 deletion. In summary, the ablation of a perinuclear H3K9me-anchor can counteract the dominant muscle-specific defects provoked by a laminopathic mutation, implicating peripheral chromatin organization in the control of muscle integrity.
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| Overall design |
Total RNA-seq in synchronized L1 larval stage of Caenorhabditis elegans with the genotypes: wild-type (samples: lmn_WT_a, lmn_WT_b) , cec-4 mutant (samples: cec4_a, cec4_b), mutant lamin (samples: lmn_Y59C_a, lmn_Y59C_b) and lamin mutant with cec-4 mutant (samples: lmn_Y59C_cec4_a, lmn_Y59C_cec4_b). 50 bp single-end sequencing was done on an Illumina HiSeq 2500.
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| Contributor(s) |
Harr JC, Schmid CD, Muñoz-Jiménez C, Romero-Bueno R, Kalck V, Gonzalez-Sandoval A, Hauer MH, Padeken J, Askjaer P, Gasser SM, Mattout A |
| Citation(s) |
32139421, 34737442 |
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| Submission date |
Aug 28, 2019 |
| Last update date |
Nov 30, 2021 |
| Contact name |
Susan Gasser |
| E-mail(s) |
[email protected]
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| Organization name |
Friedrich Miescher Institute
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| Street address |
Maulbeerstrasse 66
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| City |
Basel |
| ZIP/Postal code |
4058 |
| Country |
Switzerland |
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| Platforms (1) |
| GPL18245 |
Illumina HiSeq 2500 (Caenorhabditis elegans) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE136577 |
Loss of a heterochromatin anchor rescues altered genome organization and EDMD muscle defects triggered by a laminopathy mutation |
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| Relations |
| BioProject |
PRJNA562715 |
| SRA |
SRP219531 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE136576_ceL1_mRNA_lmn_normalized.txt.gz |
939.9 Kb |
(ftp)(http) |
TXT |
| GSE136576_ceL1_mRNA_lmn_rawCounts.txt.gz |
298.1 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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