PML modulates epigenetic composition of chromatin to regulate expression of pro-metastatic genes in triple-negative breast cancer.

Autor:	Fracassi C; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy., Ugge' M; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy., Abdelhalim M; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway., Zapparoli E; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milano, Italy., Simoni M; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy., Magliulo D; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy., Mazza D; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milano, Italy., Lazarevic D; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milano, Italy., Morelli MJ; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milano, Italy., Collas P; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway., Bernardi R; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2023 Nov 10; Vol. 51 (20), pp. 11024-11039.
DOI:	10.1093/nar/gkad819
Abstrakt:	The promyelocytic leukemia (PML) protein organizes nuclear aggregates known as PML nuclear bodies (PML-NBs), where many transcription factors localize to be regulated. In addition, associations of PML and PML-NBs with chromatin are described in various cell types, further implicating PML in transcriptional regulation. However, a complete understanding of the functional consequences of PML association to DNA in cellular contexts where it promotes relevant phenotypes is still lacking. We examined PML chromatin association in triple-negative breast cancer (TNBC) cell lines, where it exerts important oncogenic functions. We find that PML associates discontinuously with large heterochromatic PML-associated domains (PADs) that contain discrete gene-rich euchromatic sub-domains locally depleted of PML. PML promotes heterochromatic organization in PADs and expression of pro-metastatic genes embedded in these sub-domains. Importantly, this occurs outside PML-NBs, suggesting that nucleoplasmic PML exerts a relevant gene regulatory function. We also find that PML plays indirect regulatory roles in TNBC cells by promoting the expression of pro-metastatic genes outside PADs. Our findings suggest that PML is an important transcriptional regulator of pro-oncogenic metagenes in TNBC cells, via transcriptional regulation and epigenetic organization of heterochromatin domains that embed regions of local transcriptional activity. (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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