Combinatorial DNMTs and EZH2 inhibition reprograms the H3K27me3 and DNAme-mediated onco-epigenome to suppress multiple myeloma proliferation
Comprehensive epigenomic studies in multiple myeloma (MM) that unravel the connections between major epigenetic regulators, their intertwined collaboration and the potential of combinatorial targeting remain limited. Utilizing ChIP-seq, ATAC-seq, RNA-seq, and DNA methylation (DNAme) data, we generated whole-genome chromatin annotations from normal plasma cells and MM patients, revealing epigenomic re-configuration affecting downstream genes involved in tumour growth and survival. Primary MM samples showed global DNA hypomethylation but site-specific hypermethylation was observed at transcription start sites, promoters, and enhancers. Moreover, increased deposition of H3K27me3 was observed in clinically relevant functional chromatin clusters. Combined EZH2 and DNMTs inhibition resulted in extensive epigenomic alterations activating apoptosis and cell cycle genes, leading to increased G2/M arrest and apoptosis in MM cell lines. Our findings provide novel insights into the role of epigenetic gene silencing in MM tumorigenesis and the interplay between the Polycomb repressive complex 2 and DNAme.
Authors
- Paul Theodor Pyl (ORCID: https://orcid.org/0000-0002-7651-883X)
- José I. Martı́n-Subero (ORCID: https://orcid.org/0000-0001-8809-5195)
- Elke De Bruyne (ORCID: https://orcid.org/0000-0003-4012-4617)
- Antonia Kalushkova (ORCID: https://orcid.org/0000-0003-4535-506X)
- Jian Jun Jin (ORCID: https://orcid.org/0000-0002-2387-3862)
- Berta Garrido-Zabala
- Alba Atienza Párraga (ORCID: https://orcid.org/0000-0002-1872-0423)
- Louella Vasquez (ORCID: https://orcid.org/0000-0002-5758-6036)
- Jan Komorowski (ORCID: https://orcid.org/0000-0002-0766-8789)
- Anqi Ma
- Helena Jernberg‐Wiklund (ORCID: https://orcid.org/0000-0002-9319-7986)
- Klev Diamanti (ORCID: https://orcid.org/0000-0002-4922-8415)
- Doroteya Raykova (ORCID: https://orcid.org/0000-0001-6452-2199)
- Aron Skaftason
- Patrick Nylund (ORCID: https://orcid.org/0000-0002-1274-4010)
- Fredrik Öberg (ORCID: https://orcid.org/0000-0003-3609-1197)
- Stefania Iliana Tziola
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Uppsala University (SE)
- Vrije Universiteit Brussel (BE)
- Swedish Collegium for Advanced Study (SE)
- Lund University (SE)
- Science for Life Laboratory (SE)
- Institute of Computer Science (PL)
- Medivir (Sweden) (SE)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Icahn School of Medicine at Mount Sinai (US)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-08-27
- DOI
- https://doi.org/10.1038/s41598-025-17093-z
- Citations
- 2
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Amgen
- Bristol-Myers Squibb
- Celgene
- European Commission
- Cancerfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Uppsala Universitet
- Science for Life Laboratory
- National Institutes of Health