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Combinatorial DNMTs and EZH2 inhibition reprograms the H3K27me3 and DNAme-mediated onco-epigenome to suppress multiple myeloma proliferation

Atienza Párraga, Alba ; Nylund, Patrick ; Diamanti, Klev ; Garrido-Zabala, Berta ; Tziola, Stefania Iliana ; Vasquez, Louella LU ; Pyl, Paul Theodor LU ; Raykova, Doroteya ; Skaftason, Aron and Ma, Anqi , et al. (2025) In Scientific Reports 15(1).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
15
issue
1
article number
31568
publisher
Nature Publishing Group
external identifiers
  • pmid:40866476
  • scopus:105014201630
ISSN
2045-2322
DOI
10.1038/s41598-025-17093-z
language
English
LU publication?
yes
id
5f5b4fe7-59c4-41f8-9574-3ef6a4f9b723
date added to LUP
2025-10-03 09:25:49
date last changed
2025-10-04 03:00:07
@article{5f5b4fe7-59c4-41f8-9574-3ef6a4f9b723,
  abstract     = {{<p>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.</p>}},
  author       = {{Atienza Párraga, Alba and Nylund, Patrick and Diamanti, Klev and Garrido-Zabala, Berta and Tziola, Stefania Iliana and Vasquez, Louella and Pyl, Paul Theodor and Raykova, Doroteya and Skaftason, Aron and Ma, Anqi and Jin, Jian and Martín-Subero, José Ignacio and Öberg, Fredrik and De Bruyne, Elke and Komorowski, Jan and Jernberg Wiklund, Helena and Kalushkova, Antonia}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Combinatorial DNMTs and EZH2 inhibition reprograms the H3K27me3 and DNAme-mediated onco-epigenome to suppress multiple myeloma proliferation}},
  url          = {{http://dx.doi.org/10.1038/s41598-025-17093-z}},
  doi          = {{10.1038/s41598-025-17093-z}},
  volume       = {{15}},
  year         = {{2025}},
}