Lamin B1 acetylation slows the G1 to S cell cycle transition through inhibition of DNA repair
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture, Fibroblast
SUBMITTER: 
Laura Murray
LAB HEAD: Ileana M. Cristea
PROVIDER: PXD022974 | Pride | 2021-01-08
REPOSITORIES: Pride
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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.
2020-11-10 | GSE139884 | GEO
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.
2018-08-30 | GSE96033 | GEO
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.
2017-08-16 | GSE98529 | GEO
Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5’ ends, RNA Polymerases II and III and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins and DNA replication origins). To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members as well as with cellular constituents such as nuclear matrix proteins, key transcription factors and centromere components implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated. ChIP-chip analysis of lamin A/C and lamin B in HeLa S3 cells
2011-01-10 | E-GEOD-24382 | biostudies-arrayexpress
Project description:A-type lamins form a filamentous meshwork beneath the nuclear membrane that anchors large heterochromatic chromatin domains at the nuclear envelope. They also exist as a more dynamic, non-filamentous pool in the nuclear interior, where they interact with gene-rich euchromatin. Lamin-associated polypeptide 2 alpha (LAP2alpha) binds to and maintains the nucleoplasmic lamin pool, but the functional significance of this interaction is poorly understood. Here we investigate the genome-wide chromatin association of A-type lamins during myogenic differentiation in the presence and absence of LAP2alpha. We find that A-type lamins are significantly reorganized on chromatin upon depletion of LAP2alpha, spreading towards active chromatin and accumulating at regions of active H3K27ac and H3K4me3 histone marks close to the genes whose expression is impaired in the absence of LAP2alpha. This reorganization of A-type lamins on chromatin is accompanied by depletion of the active chromatin mark H3K27ac and a significant delay of myogenic differentiation. Thus, the interplay of lamins and LAP2alpha is crucial for proper positioning of intranuclear lamins on chromatin to allow normal myogenic differentiation. This research was funded in whole or in part by the Austrian Science Fund (FWF) to Roland Foisner: P32512-B/DOI:10.55776/P36503 https://www.doi.org/10.55776/P36503 P36503-B/DOI:10.55776/P32512 https://www.doi.org/10.55776/P32512
2024-08-08 | GSE247773 | GEO
Project description:A-type lamins form a filamentous meshwork beneath the nuclear membrane that anchors large heterochromatic chromatin domains at the nuclear envelope. They also exist as a more dynamic, non-filamentous pool in the nuclear interior, where they interact with gene-rich euchromatin. Lamin-associated polypeptide 2 alpha (LAP2alpha) binds to and maintains the nucleoplasmic lamin pool, but the functional significance of this interaction is poorly understood. Here we investigate the genome-wide chromatin association of A-type lamins during myogenic differentiation in the presence and absence of LAP2alpha. We find that A-type lamins are significantly reorganized on chromatin upon depletion of LAP2alpha, spreading towards active chromatin and accumulating at regions of active H3K27ac and H3K4me3 histone marks close to the genes whose expression is impaired in the absence of LAP2alpha. This reorganization of A-type lamins on chromatin is accompanied by depletion of the active chromatin mark H3K27ac and a significant delay of myogenic differentiation. Thus, the interplay of lamins and LAP2alpha is crucial for proper positioning of intranuclear lamins on chromatin to allow normal myogenic differentiation. This research was funded in whole or in part by the Austrian Science Fund (FWF) to Roland Foisner: P32512-B/DOI:10.55776/P36503 https://www.doi.org/10.55776/P36503 P36503-B/DOI:10.55776/P32512 https://www.doi.org/10.55776/P32512
2024-08-08 | GSE247771 | GEO
Project description:The integrity and regulation of the nuclear lamina is essential for nuclear organization and chromatin stability, with its dysregulation being linked to laminopathy diseases and cancer. Although numerous posttranslational modifications have been identified on lamins, few have been ascribed a regulatory function. Here, we establish that lamin B1 (LMNB1) acetylation at K134 is a molecular toggle that controls nuclear periphery stability, cell cycle progression, and DNA repair. LMNB1 acetylation prevents lamina disruption during herpesvirus type 1 (HSV-1) infection, thereby inhibiting virus production. We also demonstrate the broad impact of this site on laminar processes in uninfected cells. LMNB1 acetylation negatively regulates canonical nonhomologous end joining by impairing the recruitment of 53BP1 to damaged DNA. This defect causes a delay in DNA damage resolution and a persistent activation of the G1/S checkpoint. Altogether, we reveal LMNB1 acetylation as a mechanism for controlling DNA repair pathway choice and stabilizing the nuclear periphery.
| S-EPMC7913768 | biostudies-literature
Project description:Purpose: to qualify and quantify the rearrangement of interactions of nuclear lamins A/C and B with the genome, in relation to nuclearradial repositioning of loci and changes in gene expression, in HepG2 cells exposed to cyclosporin A. .To compare HepG2 cell line transcriptome profiling (RNA-seq) with radially positioning of the chromatin anchored at the nuclear periphery before and after CsA treatment. Methods: To this end, we mapped lamin A and lamin B lamina-associated domains (LADs) by chromatin immunoprecipitation-sequencing (ChIP-seq) of lamin A/C (antibody sc7292x, Santa Cruz Biotechnology) and lamin B1 (antibody ab16048, Abcam), respectively. HepG2 cells were either cultured under proliferative conditions (controls) or exposed for 3 days to 10 uM cyclosporin A. We also assesed the transcriptome by RNA-seq under each condition in duplicate cultures. Results: CsA elicits accumulation of pre-lamin A in HepG2 cells, raising the hypothesis of a global rearrangement of lamin-chromatin interactions. We show here the existence of overlapping and distinct lamin A and B lamina-associated domains (which we refer to as A- and B-LADs, respectively). Whereas B-LADs largely remain constitutive, CsA elicits the formation of facultative A-LADs. Re-localization of A-LADs occur mainly on preexisting B-LADs. However, LAD rearrangement does not correlate with systematic changes in gene expression within LADs. We find a reorganization of A- and B-LADs after CsA treatment, entailing distinct contributions of A- and B- type lamins. to genome organization. Indeed, classification of lamin A LADs and lamin B LADs into properties of ‘A-only’, ‘B-only’ and ‘A-B’ LADs show an overall loss of A-only LADs after CsA treatment. A- only and B-only LADs are highly dynamic with A-B LADs being more stable.The rearrangement of lamin association after CsA treatment correlates with repositioning of loci in the nuclear space with, notably, a loss of lamin B associated with a re-localization of loci towards the nuclear center and conversely, a gain of lamin B linked to a repositioning of loci towards the nuclear periphery. Predictions on radial repositioning of LADs, and of loci within, from 3D structural models of the genome were supported by fluorescence in situ hybridization (FISH) analyses. Conclusions: We show that, while they amply co-localize on well-conserved LADs, lamins A and B also interact with distinct genomic regions that can interchange (switch) between lamin A and B upon CsA treatment. We unveil distinct lamin A and B interactions with chromatin, suggesting complementary contributions to genome conformation. Our data suggest that and lamins A and B may differentially modulate genome organization.
2019-02-19 | GSE119631 | GEO
Project description:Lamins (A/C and B) are major constituents of the nuclear lamina (NL). Structurally conserved lamina-associated domains (LADs) are formed by genomic regions that contact the NL. Lamins are also found in the nucleoplasm, with a yet unknown function. Here we map the genome-wide localization of lamin B1 in an euchromatin-enriched fraction of the mouse genome and follow its dynamics during the epithelial-to-mesenchymal transition (EMT). Lamin B1 associates with actively expressed and open euchromatin regions, forming dynamic euchromatin lamin B1-associated domains (eLADs) of about 0.3 Mb. Hi-C data link eLADs to the 3D organization of the mouse genome during EMT and correlate lamin B1 enrichment at topologically associating domain (TAD) borders with increased border strength. Having reduced levels of lamin B1 alters the EMT transcriptional signature and compromises the acquisition of mesenchymal traits. Thus, during EMT, the process of genome reorganization in mouse involves dynamic changes in eLADs.
| S-EPMC6109041 | biostudies-literature
Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5’ ends, RNA Polymerases II and III and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins and DNA replication origins). To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members as well as with cellular constituents such as nuclear matrix proteins, key transcription factors and centromere components implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated.
2011-01-10 | GSE24382 | GEO