Huntington’s disease as a lamin B1 nuclear envelopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA587460 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10398600.fastq.gz | Fastqsanger.gz | |||
| SRR10398601.fastq.gz | Fastqsanger.gz | |||
| SRR10398602.fastq.gz | Fastqsanger.gz | |||
| SRR10398603.fastq.gz | Fastqsanger.gz | |||
| SRR10398604.fastq.gz | Fastqsanger.gz |
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Project description:Lamins, the major structural proteins within the nuclear lamina, are crucial for the functionality of cellular nucleus and their alterations are involved in the so-called laminopathies. We previously found that Huntington’s disease (HD), a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, courses with increased lamin B protein levels in specific brain regions in both mouse models and patients. We now show that these changes are mostly restricted to lamin B1, occur in striatal medium-sized spiny neurons and CA1 hippocampal neurons, and are accompanied by altered nuclear morphology, nucleocytoplasmic transport disruption and un-structuring of lamin-associated chromatin domains. Normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD results in beneficial restoring of nuclear lamina homeostasis and prevention of motor and cognitive dysfunction, opening a window for a new therapeutic approach for HD and other B1-type laminophaties.
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Project description:Lamin B1 is a component of the nuclear envelope involved in epigenetic chromatin regulation and is reduced during B cell activation and formation of lymphoid germinal centres. RNAi-mediated reduction of Lamin B1 results in spontaneous SHM as well as kappa-light chain aberrant surface expression showing that Lamin B1 is a negative epigenetic regulator of SHM. We used Affymetrix Exon 1.0 ST microarrays to detail the global programme of gene expression underlying changes induced in siRNA-treated Lamin B1low BL2 cells. siRNA-mediated reduction of nuclear Lamin B1 incorporation resulted in a general upregulation of positive cell cycle regulatory genes which in turn occurred alongside an upregulation of genes responsible for cell cycle checkpoint execution or cell cycle arrest, and were specific for LMNB1 reduction.
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Project description:Background: The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Results: Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to chromatin redistribution and decompaction. Consequently, lamina-associated domains (LADs) are detached from the nuclear periphery. The inter-chromosomal interactions and overlap between chromosome territories are increased. Moreover, Hi-C data revealed that lamin B1 is required for the integrity and segregation of chromatin compartments but not for the topologically associating domains (TADs). Using live cell single molecule tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Conclusions: Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting its crucial role in chromatin higher-order structure and chromatin dynamics.
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Project description:Although abnormal nuclear structure is an important criterion for cancer diagnostics, remarkably little is known about its relationship to tumor development. Here we report that loss of lamin B1, a determinant of nuclear architecture, plays a key role in lung cancer. We found that lamin B1 levels were reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells promoted epithelial-mesenchymal transition, cell migration, tumor growth and metastasis. Mechanistically, we show that lamin B1 recruits the polycomb repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes involved in cell migration and signaling. In particular, epigenetic derepression of the RET proto-oncogene by loss of PRC2 recruitment, and activation of the RET/p38 signaling axis, play a crucial role in mediating the malignant phenotype upon lamin B1 disruption. Importantly, loss of a single lamin B1 allele induced spontaneous lung tumor formation and RET activation. Thus, lamin B1 acts as a tumor suppressor in lung cancer, linking aberrant nuclear structure and epigenetic patterning with malignancy.
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Project description:Although abnormal nuclear structure is an important criterion for cancer diagnostics, remarkably little is known about its relationship to tumor development. Here we report that loss of lamin B1, a determinant of nuclear architecture, plays a key role in lung cancer. We found that lamin B1 levels were reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells promoted epithelial-mesenchymal transition, cell migration, tumor growth and metastasis. Mechanistically, we show that lamin B1 recruits the polycomb repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes involved in cell migration and signaling. In particular, epigenetic derepression of the RET proto-oncogene by loss of PRC2 recruitment, and activation of the RET/p38 signaling axis, play a crucial role in mediating the malignant phenotype upon lamin B1 disruption. Importantly, loss of a single lamin B1 allele induced spontaneous lung tumor formation and RET activation. Thus, lamin B1 acts as a tumor suppressor in lung cancer, linking aberrant nuclear structure and epigenetic patterning with malignancy.
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Project description:Through knocking out Lamin B1, we found that lamin B1 regulets hundreds of genes in neural progenitor cells, which underlie differentiation of neural protenitor cells
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Project description:Lamins (A/C and B) are type V intermediate filaments and constitute the major cytoskeleton component of nuclei. They are assembled forming a filamentous meshwork that is mainly located between the inner nuclear membrane and the peripheral chromatin in where they form structural and conserved elements called lamin-associated domains (LADs) that cover around 40% of the mammalian genome. However, a small fraction of lamins are also located in the nucleoplasm although is still unclear if represents a fraction that is in transit towards the nuclear membrane, a reservoir for protein turnover or they have specific functions in nuclear organization6. Here we mapped genome-wide the localization of lamin B1 from an enriched euchromatin fraction. Our analysis show for the first time that lamin B1 can be also associated with active euchromatin forming domains of about half a megabase on average in size. These euchromatin lamin B1 domains (eLADs) are constituted by active and accessible euchromatin showed by RNAseq and ATACseq. Importantly, we have analyzed its behavior at the onset of the epithelial to mesenchymal transition (EMT), a cellular transformation process essential during development and reactivated in cancer cells. Our results suggest that eLADs are dynamic and functional during EMT. Finally, Hi-C data during this cellular transformation showed changes in the frequency of chromatin contacts around the TSS in genes enriched in lamin B1 before the generation of new regulatory elements in the mesenchymal state. Taken together, these results demonstrate that not only heterochromatin but euchromatin is organized into lamin domains as well. Moreover, these eLADs are dynamic, functional and essential for chromatin organization and gene regulation during the EMT.
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Project description:Lamin B1 from OIS IMR90s
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