A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha

Gesson, Kevin; Rescheneder, Philipp; Skoruppa, Michael Peter; Haeseler, Arndt von; Dechat, Thomas; Foisner, Roland

doi:10.1101/gr.196220.115

Cited by 175 publications

(245 citation statements)

References 61 publications

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“…This not only maintains the integrity of the nuclear periphery but also tethers gene-poor CTs since aneuploid CT18 (in Lamin B2-depleted cells) disengages from the nuclear lamina and moves further into the nuclear interior. In the nucleoplasm, Lamins associate with chromatin organizers—CTCF, BANF1, and Lamina-associated polypeptide (LAP2α/β) that assist chromatin organization (Dechat et al 2000; Gesson et al 2016; Yusufzai et al 2004). This is likely to impinge on the spatial organization of gene-rich CTs such as CT19 toward the nuclear interior.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal aneuploidies induced upon Lamin B2 depletion are mislocalized in the interphase nucleus

et al. 2016

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Chromosome territories assume non-random positions in the interphase nucleus with gene-rich chromosomes localized toward the nuclear interior and gene-poor chromosome territories toward the nuclear periphery. Lamins are intermediate filament proteins of the inner nuclear membrane required for the maintenance of nuclear structure and function. Here, we show using whole-genome expression profiling that Lamin A/C or Lamin B2 depletion in an otherwise diploid colorectal cancer cell line (DLD1) deregulates transcript levels from specific chromosomes. Further, three-dimensional fluorescence in situ hybridization (3D-FISH) analyses of a subset of these transcriptionally deregulated chromosome territories revealed that the diploid chromosome territories in Lamin-depleted cells largely maintain conserved positions in the interphase nucleus in a gene-density-dependent manner. In addition, chromosomal aneuploidies were induced in ~25 % of Lamin A/C or Lamin B2-depleted cells. Sub-populations of these aneuploid cells consistently showed a mislocalization of the gene-rich aneuploid chromosome 19 territory toward the nuclear periphery, while gene-poor aneuploid chromosome 18 territory was mislocalized toward the nuclear interior predominantly upon Lamin B2 than Lamin A/C depletion. In addition, a candidate gene locus ZNF570 (Chr.19q13.12) significantly overexpressed upon Lamin B2 depletion was remarkably repositioned away from the nuclear lamina. Taken together, our studies strongly implicate an overarching role for Lamin B2 in the maintenance of nuclear architecture since loss of Lamin B2 relieves the spatial positional constraints required for maintaining conserved localization of aneuploid chromosome territories in the interphase nucleus.Electronic supplementary materialThe online version of this article (doi:10.1007/s00412-016-0580-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Chromosomal aneuploidies induced upon Lamin B2 depletion are mislocalized in the interphase nucleus

et al. 2016

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“…This modification can be visualized by microscopy (Figure 1B, C) or mapped genome-wide (Figure 1D). LADs can also be mapped by chromatin immunoprecipitation (ChIP) (Handoko et al, 2011), but this has been technically challenging for reasons that are only partially understood (Gesson et al, 2016; Lund et al, 2015). …”

Section: Definition and Characteristics Of Ladsmentioning

confidence: 99%

Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression

Steensel

Belmont

2017

Cell

909

851

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In metazoan cell nuclei, hundreds of large chromatin domains are in close contact with the nuclear lamina. Such lamina-associated domains (LADs) are thought to help organize chromosomes inside the nucleus and have been associated with gene repression. Here, we discuss the properties of LADs, the molecular mechanisms that determine their association with the nuclear lamina, their dynamic links with other nuclear compartments, and their proposed roles in gene regulation.

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“…Recently, deregulation of H3K27me3 in HGPS cells has been linked to impaired interaction of progerin with lamina-associated polypeptide-α (LAP2α). This protein binds tightly to lamin A, facilitating the interaction of lamin A with euchromatin (Gesson, Rescheneder et al 2016). In fact, the chromatin immunoprecipitation (ChIP) profile of lamin A/C shows strong overlap with that of LAP2α (Gesson, Rescheneder et al 2016).…”

Section: Molecular Mechanisms Behind Cellular Decline In Hgpsmentioning

confidence: 99%

“…This protein binds tightly to lamin A, facilitating the interaction of lamin A with euchromatin (Gesson, Rescheneder et al 2016). In fact, the chromatin immunoprecipitation (ChIP) profile of lamin A/C shows strong overlap with that of LAP2α (Gesson, Rescheneder et al 2016). Consistent with this data, LAP2α-deficient cells exhibit reduced binding of lamin A/C to euchromatic domains.…”

Section: Molecular Mechanisms Behind Cellular Decline In Hgpsmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

227

210

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Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.

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A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha

Cited by 175 publications

References 61 publications

Chromosomal aneuploidies induced upon Lamin B2 depletion are mislocalized in the interphase nucleus

Chromosomal aneuploidies induced upon Lamin B2 depletion are mislocalized in the interphase nucleus

Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression

Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

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