Dataset Information

Comparative ASCL1 interactome analysis reveals CDK2-Cyclin A2 as suppressors of differentiation in MYCN-amplified neuroblastoma

ABSTRACT: Neuroblastoma is a heterogeneous paediatric cancer arising from developmentally arrested neuronal precursors, where restoring differentiation offers therapeutic promise. ASCL1, a pro-neural transcription factor, is widely expressed in neuroblastoma and can drive either proliferation or differentiation depending on the cellular context. Here, we show that distinct MYCN-amplified neuroblastoma cell lines exhibit differing cell cycle and differentiation responses to ASCL1 overexpression. By comparing genome-wide ASCL1 chromatin binding, transcriptional changes, and protein-protein interactions, we found that ASCL1 binds more extensively to neuronal proteins in a cell line that is more susceptible to ASCL1-driven differentiation, but associates with cell cycle regulators in less responsive cells. We show that CDK2-Cyclin A2 bind ASCL1 in less responsive cells, with CDK-mediated phosphorylation of ASCL1 limiting the ability of ASCL1 to drive differentiation. Our study reveals that context-dependent interactions of ASCL1 with protein partners on the chromatin control its ability to re-engage a differentiation program in neuroblastoma.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neuroblast Division, Cell Culture

DISEASE(S): Neuroblastoma

SUBMITTER: Valar Nila Roamio Franklin

LAB HEAD: Anna Philpott

PROVIDER: PXD056448 | Pride | 2026-04-07

REPOSITORIES: Pride

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			Action	DRS
	Lumos_ASCL1_qPLEX-RIME.msf	Msf
	Lumos_ASCL1_qPLEX-RIME_FR-01.raw	Raw
	Lumos_ASCL1_qPLEX-RIME_FR-02.raw	Raw
	Lumos_ASCL1_qPLEX-RIME_FR-03.raw	Raw
	Lumos_ASCL1_qPLEX-RIME_FR-04.raw	Raw

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Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.

Dataset Information

Comparative ASCL1 interactome analysis reveals CDK2-Cyclin A2 as suppressors of differentiation in MYCN-amplified neuroblastoma

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