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Lamin A/C-EZH2 interaction in breast cancer cells

ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is a developmentally conserved cell biological program adopted by cancer cells to metastasize to different organs. In this process, compact, cobblestone-shaped epithelial cells transform into more slender-shaped mesenchymal cells. Throughout metastasis, cells reside at various stages along the E-M spectrum. Epithelial cells are not necessarily converted to mesenchymal cells, as cells in the E-M continuum exhibit greater survival advantages and better metastatic ability than complete mesenchymal forms. During metastasis, epithelial cells traverse through narrow capillaries, inducing nucleus rupture. The nucleus is protected by type V intermediate filament proteins, Lamins, in the inner nuclear membrane, providing structural integrity, facilitating genome organization, and acting as an impediment to cell migration. Therefore, Lamin expression is downregulated to facilitate nuclear compliance during EMT, serving as a precursor for metastasis. Here, we aim to address the mechanism of Lamin downmodulation and its role in genome organization during EMT. We have attempted to address these questions in three independent and well-established breast cancer cell lines representing cells at specific stages of the EM spectrum, providing a paradigm to elucidate the role of Lamins in genome organization and function during EMT.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Kundan Sengupta

LAB HEAD: Kundan Sengupta

PROVIDER: PXD060831 | Pride | 2025-12-23

REPOSITORIES: Pride

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			Action	DRS
	07262024_Balaji_KS_MCF7_GFP.group	Other
	07262024_Balaji_KS_MCF7_GFP.wiff	Wiff
	07262024_Balaji_KS_MCF7_GFP.wiff.scan	Wiff
	07262024_Balaji_KS_MCF7_TWIST.group	Other
	07262024_Balaji_KS_MCF7_TWIST.wiff	Wiff

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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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Lamin A/C-EZH2 interaction in breast cancer cells

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