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Updated: Jan 8, 2026
Multiplexed Analysis of Retinal Gene Expression and Chromatin Accessibility Using scRNA-Seq and scATAC-Seq
Published on: March 12, 2021
Differential chromatin accessibility response to retinoic acid in neuroblastoma with ATRX in-frame-deletions versus
Federica Lorenzi1, Matthew Shipley2, Luke Deane2
1Developmental Oncology Group, Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5AG, United Kingdom; Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, United Kingdom.
Abstract:
Neuroblastoma is a childhood cancer, arising in the developing sympathetic nervous system. Differentiation therapy with 13-cis-retinoic acid (RA) is given to children with neuroblastoma to prevent relapse, however there is little understanding of which patients benefit. ATRX alterations are identified in 10 % of high-risk neuroblastomas and associated with poor outcomes. The commonest type of ATRX alterations in neuroblastoma are in-frame multi-exon deletions, followed by nonsense mutations predicted to result in loss-of-function (ATRX LoF). We treated paired ATRX wild-type and LoF neuroblastoma cell-lines with RA: cells with ATRX LoF fail to upregulate direct RA target genes and show reduced chromatin accessibility differentiation and development related genes following RA treatment. Conversely, neuroblastoma models with in-frame deletions mount an appropriate epigenetic response to RA. Taken together this shows that the mechanism of differentiation in ATRX-altered neuroblastoma depends on the type of ATRX alteration, with implications relating to both oncogenesis and therapeutic response.
Insights
Differentiation therapy for neuroblastoma (a childhood cancer) response depends on the type of ATRX alteration. Loss-of-function ATRX alterations prevent proper gene regulation by retinoic acid (RA), impacting treatment effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma is a pediatric cancer of the sympathetic nervous system.
- Differentiation therapy with 13-cis-retinoic acid (RA) is used to prevent relapse, but patient benefit is poorly understood.
- ATRX alterations occur in 10% of high-risk neuroblastomas, correlating with poor outcomes.
Purpose of the Study:
- To investigate how different types of ATRX alterations affect neuroblastoma response to RA differentiation therapy.
- To elucidate the molecular mechanisms underlying therapeutic resistance or sensitivity in ATRX-altered neuroblastomas.
Main Methods:
- Comparison of paired ATRX wild-type and ATRX loss-of-function (LoF) neuroblastoma cell lines.
- Treatment with 13-cis-retinoic acid (RA).
- Analysis of gene expression (RA target genes) and chromatin accessibility.
Main Results:
- Neuroblastoma cells with ATRX LoF mutations failed to upregulate direct RA target genes after RA treatment.
- ATRX LoF cells exhibited reduced chromatin accessibility in differentiation and development-related genes.
- Neuroblastoma models with in-frame ATRX deletions showed an appropriate epigenetic response to RA.
Conclusions:
- The mechanism of RA-induced differentiation in ATRX-altered neuroblastoma is dependent on the specific type of ATRX alteration.
- Understanding ATRX alteration type is crucial for predicting therapeutic response and informing oncogenesis insights.
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