Converging genetic and epigenetic drivers of paediatric acute lymphoblastic leukaemia identified by an information-theoretic analysis.
CCAAT-Enhancer-Binding Proteins
/ genetics
Child
Core Binding Factor Alpha 2 Subunit
/ genetics
Cytogenetic Analysis
DNA Methylation
Entropy
Epigenesis, Genetic
Gene Editing
Gene Expression Regulation, Neoplastic
Humans
Models, Theoretical
Oncogene Proteins, Fusion
/ genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
RNA-Seq
Single-Cell Analysis
Stochastic Processes
Ubiquitin-Protein Ligases
/ genetics
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
31
01
2019
accepted:
18
02
2021
pubmed:
17
4
2021
medline:
12
5
2021
entrez:
16
4
2021
Statut:
ppublish
Résumé
In cancer, linking epigenetic alterations to drivers of transformation has been difficult, in part because DNA methylation analyses must capture epigenetic variability, which is central to tumour heterogeneity and tumour plasticity. Here, by conducting a comprehensive analysis, based on information theory, of differences in methylation stochasticity in samples from patients with paediatric acute lymphoblastic leukaemia (ALL), we show that ALL epigenomes are stochastic and marked by increased methylation entropy at specific regulatory regions and genes. By integrating DNA methylation and single-cell gene-expression data, we arrived at a relationship between methylation entropy and gene-expression variability, and found that epigenetic changes in ALL converge on a shared set of genes that overlap with genetic drivers involved in chromosomal translocations across the disease spectrum. Our findings suggest that an epigenetically driven gene-regulation network, with UHRF1 (ubiquitin-like with PHD and RING finger domains 1) as a central node, links genetic drivers and epigenetic mediators in ALL.
Identifiants
pubmed: 33859388
doi: 10.1038/s41551-021-00703-2
pii: 10.1038/s41551-021-00703-2
pmc: PMC8370714
mid: NIHMS1675463
doi:
Substances chimiques
CCAAT-Enhancer-Binding Proteins
0
Core Binding Factor Alpha 2 Subunit
0
Oncogene Proteins, Fusion
0
TEL-AML1 fusion protein
0
UHRF1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
360-376Subventions
Organisme : NIDDK NIH HHS
ID : DP1 DK119129
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA054358
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA065438
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG006282
Pays : United States
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