Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model

Harr, Jennifer C.; Schmid, Christoph D.; Muñoz-Jiménez, Celia; Romero-Bueno, Raquel; Kalck, Véronique; Gonzalez‐Sandoval, Adriana; Hauer, M.; Padeken, Jan; Askjaer, Peter; Mattout, Anna; Gasser, Susan M.

doi:10.1101/gad.332213.119

Cited by 40 publications

(48 citation statements)

References 59 publications

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“…19 Lamin A, a nuclear lamina structural protein like lamin B, is critical for the stabilization of retinoblastoma tumour suppressor proteins pRb and p107. [20][21][22] These discoveries suggest that Lamin A/B might be closely related to the tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

LMNA functions as an oncogene in hepatocellular carcinoma by regulating the proliferation and migration ability

Liu

Kan

et al. 2020

J Cellular Molecular Medi

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The role of the LMNA gene in the development and progression of hepatocellular carcinoma (HCC) and the associated molecular mechanism is not yet clear. Therefore, the purpose of this study was to evaluate the relationship between LMNA and HCC. LMNA gene expression in normal tissues and corresponding tumours was evaluated and the Kaplan–Meier survival analysis was performed. Next, the LMNA gene was knocked out in the 293T and HepG2 cell lines using the CRISPR/Cas9 technique. Subsequently, the proliferation, migration and colony formation rate of the two LMNA knockout cell lines were analysed. Finally, the molecular mechanism affecting the tumorigenesis due to the loss of the LMNA gene was evaluated. The results showed that the LMNA gene was abnormally expressed in many tumours, and the survival rate of the HCC patients with a high expression of the LMNA gene was significantly reduced compared with the rate in patients with a low LMNA expression. The knockout of the LMNA gene in the HCC cell line HepG2 resulted in a decreased tumorigenicity, up‐regulation of the P16 expression and down‐regulation of the CDK1 expression. These findings suggested that LMNA might function as an oncogene in HCC and provided a potential new target for the diagnosis and treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

LMNA functions as an oncogene in hepatocellular carcinoma by regulating the proliferation and migration ability

Liu

Kan

et al. 2020

J Cellular Molecular Medi

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“…Interestingly, such chromatin structural changes were accompanied by chromatin decondensation and reduction in the repressive HP1 and H3K9me3 marks [15][16][17][18][19] . Further…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, variations in lamin A/C levels, induced by either its up-or down regulation, or as observed in laminopathy-associated mutations in lamin A/C, drive heterochromatin detachment from the nuclear lamina 13,14 . This was accompanied by chromatin de-condensation and reduced levels of HP1 and H3K9me3 repressive marks in mammals 15,16 , C. elegans 17 as well as in Drosophila cells 18,19 . Taken together, these findings suggested that LADs are specifically sensitive to the levels of lamin A/C at the nuclear lamina.…”

Section: Introductionmentioning

confidence: 99%

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Pavlov¹,

Lorber²,

Bajpai³

et al. 2020

Preprint

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Packaging of the chromatin within the nucleus serves as an important factor in the regulation of transcriptional output. However, information on chromatin architecture on nuclear scale in fully differentiated cells, under physiological conditions and in live organisms, is largely unavailable. Here, we imaged nuclei and chromatin in muscle fibers of live, intact Drosophila larvae. In contrast to the common view that chromatin is distributed throughout the nuclear volume, we show that the entire chromatin, including active and repressed regions, forms a peripheral layer underneath the nuclear lamina, leaving a chromatin-devoid compartment at the nucleus center. Importantly, visualization of nuclear compartmentalization required imaging of un-fixed nuclei embedded within their intrinsic tissue environment, with preserved nuclear volume. Upon fixation of similar muscle nuclei, we observed an average of three-fold reduction in nuclear volume caused by dehydration and evidenced by nuclear flattening. In these conditions, the peripheral chromatin layer was not detected anymore, demonstrating the importance of preserving native biophysical tissue environment. We further show that nuclear compartmentalization is sensitive to the levels of lamin C, since over-expression of lamin C-GFP in muscle nuclei resulted in detachment of the peripheral chromatin layer from the lamina and its collapse into the nuclear center. Computer simulations of chromatin distribution recapitulated the peripheral chromatin organization observed experimentally, when binding of lamina associated domains (LADs) was incorporated with chromatin selfattractive interactions. Reducing the number of LADs led to collapse of the chromatin, similarly to our observations following lamin C over-expression. Taken together, our findings reveal a novel mode of mesoscale organization of chromatin within the nucleus in a live organism, in which the chromatin forms a peripheral layer separated from the nuclear interior.This architecture may be essential for robust transcriptional regulation in fully differentiated cells.

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“…Indeed, C. elegans has 269,049 GATC sequences per haploid genome, corresponding to an average of one site for every 374 bp and a median of 210 bp ( Gómez-Saldivar et al 2016a ). In C. elegans , DamID has been used to study the genomic footprint of the DAF-16 transcription factor ( Schuster et al 2010 ), and large-scale interactions between the genome and the nuclear periphery ( Towbin et al 2012 ; Sharma et al 2014 ; Cabianca et al 2019 ; Harr et al 2020 ).…”

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confidence: 99%

Tissue-Specific Transcription Footprinting Using RNA PoI DamID (RAPID) in Caenorhabditis elegans

et al. 2020

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Differential gene expression across cell types underlies the development and cell physiology in multicellular organisms. C. elegans is a powerful, extensively used model to address these biological questions. A remaining bottleneck relates, however, to the difficulty to obtain comprehensive tissue-specific gene transcription data, since available methods are still challenging to execute and/or require large worm populations. Here, we introduce the RNAPol DamID (RAPID) approach, in which the Dam methyltransferase is fused to a ubiquitous RNA polymerase subunit in order to create transcriptional footprints via methyl marks on the DNA of transcribed genes. To validate the method, we determined the polymerase footprints in whole animals, sorted embryonic blastomeres and in different tissues from intact young adults by driving Dam fusion expression tissue-specifically. We obtained meaningful transcriptional footprints in line with RNA-seq studies in whole animals or specific tissues. To challenge the sensitivity of RAPID and demonstrate its utility to determine novel tissue-specific transcriptional profiles, we determined the transcriptional footprints of the pair of XXX neuroendocrine cells, representing 0.2% of the somatic cell content of the animals. We identified 2362 candidate genes with putatively active transcription in XXX cells, among which the few known markers for these cells. Using transcriptional reporters for a subset of new hits, we confirmed that the majority of them were expressed in XXX and identified novel XXX-specific markers. Taken together, our work establishes RAPID as a valid method for the determination of polymerase footprints in specific tissues of C. elegans without the need for cell sorting or RNA tagging.

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Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model

Cited by 40 publications

References 59 publications

LMNA functions as an oncogene in hepatocellular carcinoma by regulating the proliferation and migration ability

LMNA functions as an oncogene in hepatocellular carcinoma by regulating the proliferation and migration ability

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Tissue-Specific Transcription Footprinting Using RNA PoI DamID (RAPID) in Caenorhabditis elegans

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