Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains

Pascual-Reguant, Laura; Blanco, Enrique; Galan, Silvia; Dily, François Le; Cuartero, Yasmina; Serra-Bardenys, Gemma; Carlo, V. Di; Iturbide, Ane; Cebrià-Costa, Joan Pau; Nonell, Lara; Herreros, Antonio Garcı́a de; Croce, Luciano Di; Martí‐Renom, Marc A.; Peiró, Sandra

doi:10.1038/s41467-018-05912-z

Cited by 74 publications

(84 citation statements)

References 59 publications

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“…Our results extend previous findings [27,32,33] and may be explained by dynamic lamin interactions with chromatin [34]. They also support the view that lamin B (in addition to lamin A 12 [13,15,18,35,36],) may interact with chromatin in the nuclear interior, such as gene-poor perinucleolar heterochromatin [37] or euchromatic regions [17].…”

Section: Discussionsupporting

confidence: 91%

“…While lamins A and B are localized at the nuclear lamina, a nucleoplasmic pool of lamin A also interacts with euchromatic regions [12][13][14][15][16]. Intriguingly, a minor fraction of lamin B1 has also been found in the nuclear interior also in association with euchromatin [17]. These observations suggest that alterations in lamin-genome interactions may impact genome organization at the nuclear periphery and in the nuclear interior.…”

Section: Introductionmentioning

confidence: 94%

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Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Forsberg

Brunet

Ali

et al. 2019

Nucleus

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Immunosuppressive drugs such as cyclosporin A (CsA) can elicit hepatotoxicity by affecting gene expression. Here, we address the link between CsA and large-scale chromatin organization in HepG2 hepatocarcinoma cells. We show the existence of lamina-associated domains (LADs) interacting with lamin A, lamin B, or both. These ‘A-B’, ‘A-only’ and ‘B-only’ LADs display distinct fates after CsA treatment: A-B LADs remain constitutive or lose A, A-only LADs mainly lose A or switch to B, and B-only LADs remain B-only or acquire A. LAD rearrangement is overall uncoupled from changes in gene expression. Three-dimensional (3D) genome modeling predicts changes in radial positioning of LADs as LADs switch identities, which are corroborated by fluorescence in situ hybridization. Our results reveal interplay between A- and B-type lamins on radial locus positioning, suggesting complementary contributions to large-scale genome architecture. The data also unveil a hitherto unsuspected impact of cytotoxic drugs on genome conformation.Abbreviations: ChIP-seq: chromatin immunoprecipitation sequencing; CsA: cyclosporin A; FISH; fluorescence in situ hybridization; ICMT: isoprenylcysteine methyltransferase; LAD: lamina-associated domain; TAD: topologically-associated domain

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 94%

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Forsberg

Brunet

Ali

et al. 2019

Nucleus

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“…The loss of LMNB1 typifies all senescence conditions [57] and triggers a deep re-modelling of lamina-associated domains (LADs) [44,56]. LADs re-modelling contributes to re-organizing not only heterochromatin and SAHF [44], but also euchromatin (eLADs) [58]. Moreover, the knockdown of LMNB1 in proliferating cells promotes the premature senescence and gives rise to a H3K4me3 /H3K27me3 re-organization similarly to what observed in RS, OIS and HGPS [56].…”

Section: Nuclear Laminsmentioning

confidence: 83%

The Histone Code of Senescence

Paluvai

Giorgio

Brancolini

2020

Cells

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Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

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“…Lamin B1 is classically associated to large heterochromatin domains called lamin associated domains (LADs), characterized by low gene expression levels 24 . Recently, however, LADs have been linked to actively-transcribed euchromatic regions 25 . Therefore, we set out to study whether increased lamin B1 levels could alter their chromatin binding landscape.…”

Section: Increased Lamin B1 Levels Correlates With Alterations In Nucmentioning

confidence: 99%

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Alcalà-Vida

Garcia‐Forn

Creus-Muncunill

et al. 2020

Preprint

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Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntington's disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.Keywords: chromatin accessibility, LAD, R6/1 mouse, nuclear morphology, nuclear permeability of the polyglutamine chain at the amino terminus of the huntingtin (Htt) protein inducing selfassociation and aggregation. Consequently, mutant Htt (mHtt) loses its biological functions and becomes toxic 13 . In HD, medium-sized spiny neurons (MSNs), the GABAergic output projection neurons that account for the vast majority (90-95%) of all striatal neurons, are mainly affected. Although motor symptoms are the most prominent, psychiatric alterations and cognitive decline appear first in HD patients, which become more evident as the disease progresses. Cognitive deficits are related to the dysfunction of the corticostriatal pathway and the hippocampus and, together with motor deficits, have been replicated in most HD mouse models 14 .Molecular mechanisms leading to nuclear lamina alterations in neurons expressing mHtt remain to be elucidated. Previous results from our lab suggested that decreased levels of the pro-apoptotic kinase PKC would lead to an aberrant accumulation of lamin B 15 which, in turn, could have a significant influence in the nuclear lamina structure 16,17 . Therefore, here we sought to deeply characterize the impact of lamin alterations in HD brain at physiological (studying nuclear lamina morphology and nucleo-cytoplasmic transport), transcriptomic (by generating RNA-sequencing (RNA-seq) data) and epigenetic (analyzing lamin chromatin binding and chromatin accessibility) levels by using the R6/1 transgenic mouse model of HD and human post-mortem brain samples. ResultsLamin B levels are increased in a region-specific manner in HD brain. Lamin B1, B2, and A/C protein levels were analyzed in the striatum, cortex and hippocampus of wild-type and R6/1 mice, a transgenic mouse model of HD over-expressing the exon 1 of the human mutant huntingtin 18 , at different ages. Western blot a...

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Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains

Cited by 74 publications

References 59 publications

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

The Histone Code of Senescence

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

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