Nuclear lamina maintains global spatial organization of chromatin in Drosophila cultured cells

Ulianov, Sergey V.; Doronin, Semen A.; Khrameeva, Ekaterina E.; Kos, Pavel; Starikov, Sergey S.; Galitsyna, Aleksandra A.; Luzhin, Artem V; Gelfand, Mikhail S.; Chertovich, Alexander V.; Razin, S. V.; Shevelyov, Yuri Y.

doi:10.1109/bibm.2018.8621123

Cited by 2 publications

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“…Thus, we validated, by co-immunoprecipitation experiments, RNF220 and lamin B1 protein association and we demonstrated that AR-LAD mutations, particularly p.R365Q, significantly diminish RNF220 binding to lamin B1.. Lamin B1, encoded by the LMNB1 gene, is a member of the intermediate filament protein family and is part of the nuclear lamina, the protein meshwork lining the inner surface of the nuclear envelope 32,33 . Nuclear lamina not only provides mechanical support to the nucleus, but also plays a dynamic role in the organization and regulation of chromatin, transcription, DNA replication, DNA repair and epigenetic modifications [34][35][36][37][38][39][40] . Lamin B1 is critical for proper brain development [41][42][43][44][45] and the entire CNS is susceptible to modifications of LMNB1 levels 11,12,[46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Sferra

Fortugno

Motta

et al. 2021

Brain

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Leukodystrophies are a heterogeneous group of rare inherited disorders that involve preferentially the white matter of the central nervous system (CNS). These conditions are characterized by a primary glial cell and myelin sheath pathology of variable etiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in 5 large consanguineous nuclear families allowed to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report on two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the cause underlying a novel form of leukodystrophy with ataxia and sensorineural deafness having fibrotic cardiomyopathy and hepatopathy as associated features, in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation, and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology: mutations primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness, and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Sferra

Fortugno

Motta

et al. 2021

Brain

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A global high-density chromatin interaction network reveals functional long-range and trans-chromosomal relationships

Lohia

Gillis

2022

Genome Biol

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Background Chromatin contacts are essential for gene-expression regulation; however, obtaining a high-resolution genome-wide chromatin contact map is still prohibitively expensive owing to large genome sizes and the quadratic scale of pairwise data. Chromosome conformation capture (3C)-based methods such as Hi-C have been extensively used to obtain chromatin contacts. However, since the sparsity of these maps increases with an increase in genomic distance between contacts, long-range or trans-chromatin contacts are especially challenging to sample. Results Here, we create a high-density reference genome-wide chromatin contact map using a meta-analytic approach. We integrate 3600 human, 6700 mouse, and 500 fly Hi-C experiments to create species-specific meta-Hi-C chromatin contact maps with 304 billion, 193 billion, and 19 billion contacts in respective species. We validate that meta-Hi-C contact maps are uniquely powered to capture functional chromatin contacts in both cis and trans. We find that while individual dataset Hi-C networks are largely unable to predict any long-range coexpression (median 0.54 AUC), meta-Hi-C networks perform comparably in both cis and trans (0.65 AUC vs 0.64 AUC). Similarly, for long-range expression quantitative trait loci (eQTL), meta-Hi-C contacts outperform all individual Hi-C experiments, providing an improvement over the conventionally used linear genomic distance-based association. Assessing between species, we find patterns of chromatin contact conservation in both cis and trans and strong associations with coexpression even in species for which Hi-C data is lacking. Conclusions We have generated an integrated chromatin interaction network which complements a large number of methodological and analytic approaches focused on improved specificity or interpretation. This high-depth “super-experiment” is surprisingly powerful in capturing long-range functional relationships of chromatin interactions, which are now able to predict coexpression, eQTLs, and cross-species relationships. The meta-Hi-C networks are available at https://labshare.cshl.edu/shares/gillislab/resource/HiC/.

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Nuclear lamina maintains global spatial organization of chromatin in Drosophila cultured cells

Cited by 2 publications

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Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

A global high-density chromatin interaction network reveals functional long-range and trans-chromosomal relationships

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