Laminopathies: what can humans learn from fruit flies

Pałka, Marta; Tomczak, Aleksandra; Grabowska, Katarzyna; Machowska, Magdalena; Piekarowicz, Katarzyna; Rzepecka, Dorota; Rzepecki, Ryszard

doi:10.1186/s11658-018-0093-1

Cited by 22 publications

(22 citation statements)

References 74 publications

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“…Lam A25 homozygotes D. melanogaster lines were obtained from the Bloomington Stock Center (BSC). The original lamin-mutant line had genotype Lam A25 pr 1 /CyO; st 1 (BSC, #25092). For easier identification of homozygous mutant larvae, the original Lam A25 pr 1 /CyO; st 1 line was crossed with flies expressing green fluorescent protein (GFP) in the balancer chromosome -w*; L 1 Pin 2 /CyO,P{w +mC = GAL4 -Kr.C}DC3,P{w +mC = UAS-GFP.S65T}DC7 (BSC, #5194) ( Figure 1).…”

Section: Fly Stocks and The Crossing Scheme To Obtainmentioning

confidence: 99%

“…For easier identification of homozygous mutant larvae, the original Lam A25 pr 1 /CyO; st 1 line was crossed with flies expressing green fluorescent protein (GFP) in the balancer chromosome -w*; L 1 Pin 2 /CyO,P{w +mC = GAL4 -Kr.C}DC3,P{w +mC = UAS-GFP.S65T}DC7 (BSC, #5194) ( Figure 1). The experimental homozygous lamin-mutant flies had the genotype w*; Lam A25 pr 1 ; st 1 . Canton-S (BSC, #64349) flies were used as the wild-type (wt) control.…”

Section: Fly Stocks and The Crossing Scheme To Obtainmentioning

confidence: 99%

“…Genomic DNA was extracted from ten w*; Lam A25 pr 1 ; st 1 homozygous larvae using the DNeasy Blood & Tissue Kit (#69506, Qiagen, Hilden, Germany). The 300-500-bp-long fragments were PCR-amplified with 12 pairs of primers (Table S1) using 2× ImmoMix reaction-mix (#25020, Bioline USA Inc., Memphis, TN, USA).…”

Section: Sequencing and Localization Of The Lam A25 Frameshift Mutationmentioning

confidence: 99%

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Reorganization of the nuclear architecture in the Drosophila melanogaster Lamin B mutant lacking the CaaX box

Bondarenko

Sharakhov

2020

Nucleus

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Lamins interact with the nuclear membrane and chromatin but the precise players and mechanisms of these interactions are unknown. Here, we tested whether the removal of the CaaX motif from Lamin B disrupts its attachment to the nuclear membrane and affects chromatin distribution. We used Drosophila melanogaster Lam A25 homozygous mutants that lack the CaaX box. We found that the mutant Lamin B was not confined to the nuclear periphery but was distributed throughout the nuclear interior, colocalizing with chromosomes in salivary gland and proventriculus. The peripheral position of Lamin C, nuclear pore complex (NPC), heterochromatin protein 1a (HP1a), H3K9me2-and H3K27me3associated chromatin remained intact. The fluorescence intensity of the DAPI-stained peripheral chromatin significantly decreased and that of the central chromatin significantly increased in the proventriculus nuclei of the mutantflies compared to wild-type. However, the mutation had little effect on chromatin radial distribution inside highly polytenized salivary gland nuclei.

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Section: Fly Stocks and The Crossing Scheme To Obtainmentioning

confidence: 99%

Section: Fly Stocks and The Crossing Scheme To Obtainmentioning

confidence: 99%

Section: Sequencing and Localization Of The Lam A25 Frameshift Mutationmentioning

confidence: 99%

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Reorganization of the nuclear architecture in the Drosophila melanogaster Lamin B mutant lacking the CaaX box

Bondarenko

Sharakhov

2020

Nucleus

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“…Drosophila lamin C, which is the homolog of mammalian A/C type lamin, displays tissuespecific expression levels in fully differentiated cells 39,40 . Mutations in lamin A/C have been associated with aberrant chromatin organization and global detachment of chromatin from the nuclear lamina in a wide range of model organisms and tissues 15,18,19 .…”

Section: Lamin C Over-expression Disrupts Chromatin Localization At Tmentioning

confidence: 99%

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Pavlov¹,

Lorber²,

Bajpai³

et al. 2020

Preprint

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Packaging of the chromatin within the nucleus serves as an important factor in the regulation of transcriptional output. However, information on chromatin architecture on nuclear scale in fully differentiated cells, under physiological conditions and in live organisms, is largely unavailable. Here, we imaged nuclei and chromatin in muscle fibers of live, intact Drosophila larvae. In contrast to the common view that chromatin is distributed throughout the nuclear volume, we show that the entire chromatin, including active and repressed regions, forms a peripheral layer underneath the nuclear lamina, leaving a chromatin-devoid compartment at the nucleus center. Importantly, visualization of nuclear compartmentalization required imaging of un-fixed nuclei embedded within their intrinsic tissue environment, with preserved nuclear volume. Upon fixation of similar muscle nuclei, we observed an average of three-fold reduction in nuclear volume caused by dehydration and evidenced by nuclear flattening. In these conditions, the peripheral chromatin layer was not detected anymore, demonstrating the importance of preserving native biophysical tissue environment. We further show that nuclear compartmentalization is sensitive to the levels of lamin C, since over-expression of lamin C-GFP in muscle nuclei resulted in detachment of the peripheral chromatin layer from the lamina and its collapse into the nuclear center. Computer simulations of chromatin distribution recapitulated the peripheral chromatin organization observed experimentally, when binding of lamina associated domains (LADs) was incorporated with chromatin selfattractive interactions. Reducing the number of LADs led to collapse of the chromatin, similarly to our observations following lamin C over-expression. Taken together, our findings reveal a novel mode of mesoscale organization of chromatin within the nucleus in a live organism, in which the chromatin forms a peripheral layer separated from the nuclear interior.This architecture may be essential for robust transcriptional regulation in fully differentiated cells.

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“…In humans, mutations in LMNA or other nuclear lamina/envelope genes are responsible for a plethora of diseases termed laminopathies, which include muscular dystrophies, cardiomyopathy, lipodystrophies, and progeroid syndromes [10][11][12][13][14]. Two lamin genes are present in Drosophila, even if they cannot be classified in A-type or B-type lamins on the base of the homology sequence [15][16][17][18][19]. One of them, called Lamin (Lam) or Lamin Dm0 (LamDm0), has been considered the homolog of the vertebrate B-type lamin on the basis of its ubiquitous expression, while the other, called Lamin C (LamC), has been considered the homolog of vertebrate A-type lamin due to its developmentally regulated expression [20].…”

mentioning

confidence: 99%

Silencing of Euchromatic Transposable Elements as a Consequence of Nuclear Lamina Dysfunction

Cavaliere

Lattanzi

Andrenacci

2020

Cells

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Transposable elements (TEs) are mobile genomic sequences that are normally repressed to avoid proliferation and genome instability. Gene silencing mechanisms repress TEs by RNA degradation or heterochromatin formation. Heterochromatin maintenance is therefore important to keep TEs silent. Loss of heterochromatic domains has been linked to lamin mutations, which have also been associated with derepression of TEs. In fact, lamins are structural components of the nuclear lamina (NL), which is considered a pivotal structure in the maintenance of heterochromatin domains at the nuclear periphery in a silent state. Here, we show that a lethal phenotype associated with Lamin loss-of-function mutations is influenced by Drosophila gypsy retrotransposons located in euchromatic regions, suggesting that NL dysfunction has also effects on active TEs located in euchromatic loci. In fact, expression analysis of different long terminal repeat (LTR) retrotransposons and of one non-LTR retrotransposon located near active genes shows that Lamin inactivation determines the silencing of euchromatic TEs. Furthermore, we show that the silencing effect on euchromatic TEs spreads to the neighboring genomic regions, with a repressive effect on nearby genes. We propose that NL dysfunction may have opposed regulatory effects on TEs that depend on their localization in active or repressed regions of the genome.Cells 2020, 9, 625 2 of 16 (PTGS) or to repress transcription by transcriptional gene silencing (TGS). TGS is achieved by formation of heterochromatin [5], and reduction of heterochromatin results in the activation of the transcriptionally repressed regions. A global loss of heterochromatin has been described during aging and is related to the derepression of TEs [6]. For this reason, it has been hypothesized that age-associated reduction of heterochromatin determines the loss of inactivation of TE expression and the consequent mobilization. It is known that heterochromatic regions tend to be associated with the nuclear lamina (NL), a structural scaffold lining the surface of the inner nuclear membrane [7]. NL is constituted by a network of intermediate filaments and has different functions including the chromatin anchorage [8]. Lamins are the major constituents of the NL and are classified into A-and B-type lamins [9]. In humans, the A-type lamins (i.e., lamin A and lamin C) are encoded by the LMNA gene, while the B-type lamins (i.e., lamin B1 and lamin B2) are encoded by the LMNB1 and LMNB2 genes, respectively. Lamin A and lamin C are produced by alternative splicing of a common primary transcript. In humans, mutations in LMNA or other nuclear lamina/envelope genes are responsible for a plethora of diseases termed laminopathies, which include muscular dystrophies, cardiomyopathy, lipodystrophies, and progeroid syndromes [10][11][12][13][14]. Two lamin genes are present in Drosophila, even if they cannot be classified in A-type or B-type lamins on the base of the homology sequence [15][16][17][18][19]. One of them, called Lamin (Lam) o...

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Laminopathies: what can humans learn from fruit flies

Cited by 22 publications

References 74 publications

Reorganization of the nuclear architecture in the Drosophila melanogaster Lamin B mutant lacking the CaaX box

Reorganization of the nuclear architecture in the Drosophila melanogaster Lamin B mutant lacking the CaaX box

Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization

Silencing of Euchromatic Transposable Elements as a Consequence of Nuclear Lamina Dysfunction

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