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LAP2alpha facilitates myogenic gene expression by preventing spreading of nucleoplasmic lamin A/C to active chromatin regions (RNA-Seq)

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE247773 | GEO | 2024/08/08

REPOSITORIES: GEO

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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.

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LAP2alpha facilitates myogenic gene expression by preventing spreading of nucleoplasmic lamin A/C to active chromatin regions (RNA-Seq)

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