Exploring the impact of dexamethasone on gene regulation in myeloma cells.
Life Sci Alliance
; 6(9)2023 09.
Article
em En
| MEDLINE
| ID: mdl-37524526
ABSTRACT
Among glucocorticoids (GCs), dexamethasone (Dex) is widely used in treatment of multiple myelomas. However, despite a definite benefit, all patients relapse. Moreover, the molecular basis of glucocorticoid efficacy remains elusive. To determine genomic response to Dex in myeloma cells, we generated bulk and single-cell multi-omics data and high-resolution contact maps of active enhancers and target genes. We show that a minority of glucocorticoid receptor-binding sites are associated with enhancer activity gains, increased interaction loops, and transcriptional activity. We identified and characterized a predominant enhancer enriched in cohesin (RAD21) and more accessible upon Dex exposure. Analysis of four gene-specific networks revealed the importance of the CTCF-cohesin couple and the synchronization of regulatory sequence openings for efficient transcription in response to Dex. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity, in particular, lineage-specific genes. As consequences, BCL2L11-encoding BIM critical for Dex-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather up-regulated in different cells. In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dexametasona
/
Mieloma Múltiplo
Limite:
Humans
Idioma:
En
Revista:
Life Sci Alliance
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
França