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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

Recruitment to the nuclear periphery enhances repression of H3K9me2-marked genes and transposons to shape cell fate [CUT&Run]

Project description:Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the functional importance of this organization is unknown. Both the nuclear lamins and the nuclear membrane protein lamin B receptor (LBR) have been linked to heterochromatin positioning in mammals, yet embryonic stem cells (mESCs) lacking all lamins retain both LBR and H3K9me2 at the nuclear periphery. We ablated LBR in this context and show that heterochromatin detaches from the nuclear periphery in lamin + LBR quadruple knockout (QKO) cells. QKO mESCs sustain naïve pluripotency and maintain H3K9me2 at normal levels across the genome but cannot repress H3K9me2-marked genes or transposons. Further, their capacity to differentiate into epiblast-like cells (EpiLCs) is impaired. While normal EpiLCs expand H3K9me2 across the genome, QKO EpiLCs exhibit abnormal patterning of this mark. QKO cells can exit naïve pluripotency and activate epiblast-stage genes but also express markers of alternative fates including the primitive endoderm. These results establish that recruitment of H3K9me2 to the nuclear periphery controls the spatial position, dynamic remodeling, and repressive capacity of this mark to shape cell fate decisions.

2024-08-09 | GSE264603 | GEO

Recruitment to the nuclear periphery enhances repression of H3K9me2-marked genes and transposons to shape cell fate [RNAseq_shLBR]

2024-08-09 | GSE264602 | GEO

Recruitment to the nuclear periphery enhances repression of H3K9me2-marked genes and transposons to shape cell fate [RNAseq_epilc]

2024-08-09 | GSE264599 | 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

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