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Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration

ABSTRACT: Two proteins have previously been shown to be necessary and sufficient to tether heterochromatin at the nuclear envelope. The lamin B receptor (Lbr) is expressed during development, but downregulates upon rod differentiation. A second tether is the intermediate filament lamin A (LA), which is not normally expressed in murine rods.To determine how heterochromatin tethering affects the genome, we used in vivo electroporation to misexpress LA or Lbr in mature rods in the absence of degeneration, resulting in the restoration of conventional nuclear architecture. Using scRNA-seq, we show that reorganizing the nucleus via LA/Lbr misexpression has only minor effects on rod gene expression. Next, using ATAC-seq, we show that LA and Lbr similarly increase genome accessibility. Novel ATAC-seq peaks tended to distal to genes, but some peaks were associated with stress-responsive genes. Together, our data reveal that heterochromatin tethers have a global effect on genome accessibility, and suggest that LA –dependent genome reconfiguration might contribute to the stress response of rod photoreceptors.

ORGANISM(S): Mus musculus

PROVIDER: GSE240465 | GEO | 2023/10/12

REPOSITORIES: GEO

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Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration

Project description:Neurodegenerative diseases are accompanied by dynamic changes in gene expression, including the upregulation of hallmark stress-responsive genes. While the transcriptional pathways that impart adaptive and maladaptive gene expression signatures have been the focus of intense study, the role of higher order nuclear organization in this process is less clear. Here, we examine the role of the nuclear lamina in genome organization during the degeneration of rod photoreceptors. Two proteins had previously been shown to be necessary and sufficient to tether heterochromatin at the nuclear envelope. The lamin B receptor (Lbr) is expressed during development, but downregulates upon rod differentiation. A second tether is the intermediate filament lamin A (LA), which is not normally expressed in murine rods. Here, we show that in the rd1 model of retinitis pigmentosa, LA ectopically upregulates in rod photoreceptors at the onset of degeneration. LA upregulation correlated with increased heterochromatin tethering at the nuclear periphery in rd1 rods, suggesting that LA reorganizes the nucleus. To determine how heterochromatin tethering affects the genome, we used in vivo electroporation to misexpress LA or Lbr in mature rods in the absence of degeneration, resulting in the restoration of conventional nuclear architecture. Using scRNA-seq, we show that reorganizing the nucleus via LA/Lbr misexpression has relatively minor effects on rod gene expression. Next, using ATAC-seq, we show that LA and Lbr both lead to marked increases in genome accessibility. Novel ATAC-seq peaks tended to be associated with stress-responsive genes. Together, our data reveal that heterochromatin tethers have a global effect on genome accessibility, and suggest that heterochromatin tethering primes the photoreceptor genome to respond to stress.

2023-11-02 | GSE240312 | GEO

Suppression of LBR by miR-340 disrupts chromatin, promotes cell senescence, and enhances senolysis (ATAC-Seq)

Project description:The goal of this study was to identify accessible chromatin peaks in lamina-associated domains of senescent cells. To establish senescence we used ionizing radiation (IR), overexpression of miR-340-5p, and knockdown of Lamin B Receptor (LBR).One of the cellular processes influenced by microRNAs is senescence, a state of indefinite growth arrest triggered by sublethal cell damage. Here, through bioinformatic analysis and experimental validation, we identified miR-340-5p as a novel miRNA that foments cellular senescence. miR340-5p was highly abundant in diverse senescence models, and miR-340-5p overexpression in proliferating cells rendered them senescent. Among the target mRNAs, miR-340-5p prominently reduced the levels of LBR mRNA, encoding Lamin B Receptor (LBR). Loss of LBR by ectopic overexpression of miR-340-5p derepressed heterochromatin in lamina-associated domains (LADs), promoting the expression of DNA repetitive elements characteristic of senescence. Importantly, overexpressing miR-340-5p enhanced cellular sensitivity to senolytic compounds, while antagonization of miR-340-5p reduced senescent-cell markers and engendered resistance to senolytic-induced cell death. We propose that miR-340-5p can be exploited for clearing senescent cells to restore tissue homeostasis and mitigate damage by senescent cells in aging human pathologies.

2021-06-25 | GSE165465 | GEO

HSPB3 promotes myogenic differentiation by targeting the lamin B receptor.

Project description:HSPB3 is a member of the HSPB family that is absent in cycling cells. HSPB3 expression is induced by the myogenic specific transcription factor MyoD in muscle cells, where HSPB3 localizes to the nucleus. Yet, whether HSPB3 participates to muscle cell differentiation is unknown. One of the early events of cell differentiation consists in the switch between the lamin B receptor (LBR) and the lamin A/C (LMNA) tethers, which modulates chromatin remodeling and transcription. Here, we identified LBR as a specialized substrate regulated by HSPB3. HSPB3 affected the expression and nuclear distribution of LBR mimicking the changes that occur during differentiation. HSPB3 upregulation promoted the differentiation of two human muscle cell types: LHCNM2 cells, derived from satellite cells and fusion-negative rhabdomyosarcoma cells, which fail to commit to terminal differentiation. Conversely, HSPB3 depletion stabilized the LBR tether and affected the myogenic transcriptional program. Four mutations in the HSPB3 gene are linked to distal hereditary motor neuropathy and congenital myopathy with unknown mechanisms. We focused on R116P-HSPB3, which was discovered in a myopathy patient with chromatin alterations and muscle fiber disorganization. Upon overexpression in cells R116-HSPB3 formed nuclear aggregates that immobilized LBR-GFP. In LHCNM2 cells R116-HSPB3 deregulated the transcriptional program required for cytoskeleton and ECM remodeling, while activating the unfolded protein response. We propose that HSPB3 is a highly specialized chaperone that participates to muscle cell differentiation by targeting LBR. Our findings pave the way for a better understanding of HSPB3 implication in the physiology and pathology of the neuromuscular system.

2021-05-12 | GSE160027 | GEO

Suppression of LBR by miR-340 disrupts chromatin, promotes cell senescence, and enhances senolysis (RNA-Seq 2)

Project description:One of the cellular processes influenced by microRNAs is senescence, a state of indefinite growth arrest triggered by sublethal cell damage. Here, through bioinformatic analysis and experimental validation, we identified miR-340-5p as a novel miRNA that foments cellular senescence. miR340-5p was highly abundant in diverse senescence models, and miR-340-5p overexpression in proliferating cells rendered them senescent. Among the target mRNAs, miR-340-5p prominently reduced the levels of LBR mRNA, encoding Lamin B Receptor (LBR). Loss of LBR by ectopic overexpression of miR-340-5p derepressed heterochromatin in lamina-associated domains (LADs), promoting the expression of DNA repetitive elements characteristic of senescence. Importantly, overexpressing miR-340-5p enhanced cellular sensitivity to senolytic compounds, while antagonization of miR-340-5p reduced senescent-cell markers and engendered resistance to senolytic-induced cell death. We propose that miR-340-5p can be exploited for clearing senescent cells to restore tissue homeostasis and mitigate damage by senescent cells in aging human pathologies.

2021-06-25 | GSE165468 | GEO

Suppression of LBR by miR-340 disrupts chromatin, promotes cell senescence, and enhances senolysis (RNA-Seq 1)

2021-06-25 | GSE165466 | GEO

Transcriptome of LBR-null mouse kidneys

Project description:We tested overall gene expression change upon chromatin architecture disruption. RNA-seq was performed using nuclear architecture-disrupted mice carrying a loss-of-function mutation in LBR (Lbric-J/ic-J; LBR-null mice). LBR is an INM protein that tethers heterochromatin to the nuclear envelope whose level is decreased in various aging contexts.

2021-06-01 | GSE169240 | GEO

Lamin A dimer and tetramer cross-links help explain disease mutations and polymer plasticity

Project description:Lamins are intermediate filament proteins responsible for nuclear mechanical integrity. Though linked to multiple heritable diseases, lamin structure and that of other intermediate filaments remains elusive. We employed cross-linking mass spectrometry to gain structural insights into lamin A dimer and tetramer structure. While confirming the parallel coiled-coil rod, we report that, contrary to prediction, rod linker regions are highly flexible and compressible. This explains the recently reported rod shortening in the assembled polymer and aspects of intermediate filament stretch properties. We further elucidate an extended interface in lamin A tetramers where both head and tail unstructured regions flanking the rod of each dimer act as polar bridges to stabilize lamin head-to-tail assembly. Furthermore, changes in these regions between dimer and tetramer forms suggest an ordered polymer assembly. Importantly, several residues mutated in laminopathies disrupt this interface and impair assembly, potentially explaining their role in disease.

2019-07-12 | PXD008337 | Pride

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

Project description:Lamins are components of the peripheral nuclear lamina and interact with heterochromatic genomic regions, termed lamina-associated domains (LADs). In contrast to Lamin B11, lamin A/C also localizes throughout the nucleus, where it associates with the chromatin-binding protein lamina-associated polypeptide (LAP) 2alpha. Here we show lamin A/C also interacts with euchromatin, as determined by chromatin immunoprecipitation analyses of eu- and heterochromatin-enriched samples. By way of contrast, Lamin B11 was only found associated with heterochromatin. Euchromatic regions occupied by lamin A/C overlap with those bound by LAP2alpha, the depletion of which shifts binding of lamin A/C towards more heterochromatic regions. These alterations in lamin A/C chromatin interaction affect epigenetic histone marks in euchromatin without significantly affecting gene expression, while loss of lamin A/C in heterochromatic regions increased gene expression. Our data show a novel role of nucleoplasmic lamin A/C and LAP2alpha in regulating euchromatin. Examination of Lamin A/C, Lamin B1 and Lap2a DNA binding in Lap2alpha +/+ and Lap2a -/- cells and according changes in Histone modifications and gene expression

2016-01-19 | E-GEOD-70147 | biostudies-arrayexpress

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

Project description:Lamins are components of the peripheral nuclear lamina and interact with heterochromatic genomic regions, termed lamina-associated domains (LADs). In contrast to lamin B1, lamin A/C also localizes throughout the nucleus, where it associates with the chromatin-binding protein lamina-associated polypeptide (LAP) 2alpha. Here we show lamin A/C also interacts with euchromatin, as determined by chromatin immunoprecipitation analyses of eu- and heterochromatin-enriched samples. By way of contrast, lamin B1 was only found associated with heterochromatin. Euchromatic regions occupied by lamin A/C overlap with those bound by LAP2alpha, the depletion of which shifts binding of lamin A/C towards more heterochromatic regions. These alterations in lamin A/C chromatin interaction affect epigenetic histone marks in euchromatin without significantly affecting gene expression, while loss of lamin A/C in heterochromatic regions increased gene expression. Our data show a novel role of nucleoplasmic lamin A/C and LAP2alpha in regulating euchromatin. Examination of LaminA, LaminB and Lap2a DNA binding in Lap2alpha +/+ and Lap2a -/- cells and according changes in Histone modifications and gene expression

2016-01-19 | E-GEOD-70148 | biostudies-arrayexpress

Lamin b receptor regulates nuclear architecture and gene expression in olfactory neurons

Project description:Gene positioning and regulation of nuclear architecture are thought to influence gene expression. Here, we show that in mouse olfactory neurons, silent olfactory receptor (OR) genes from different chromosomes converge in a small number of heterochromatic foci. These foci are OR-exclusive and form in a cell-type-specific and differentiation- dependent manner. The aggregation of OR genes is developmentally synchronous with the downregulation of Lamin b Receptor (LBR) and can be reversed by ectopic expression of LBR in mature olfactory neurons. LBR-induced reorganization of nuclear architecture and redistribution of OR loci results in misregulation of OR transcription and disruption of the targeting specificity of the olfactory neurons. Our observations are consistent with a model of spatial regulation of OR expression and provide evidence for the instructive role of nuclear architecture and compartmentalization in gene regulation and differentiation. A complex probe was made by array capture to label mouse olfactory receptor genes by DNA FISH; this microarray data verifies the composition of that probe. Probe was made by array capture and elution from a custom olfactory receptor genomic region tiling array. Probe was verified on a chr1-4 tiling array.

2012-08-30 | E-GEOD-38488 | biostudies-arrayexpress

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