ZFTA-RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA-RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression.

A fundamental paradigm in neuroscience is that neurons represent the world through fixed tuning functions, with stable mappings from stimulus features to firing rates1. Here, we report that tuning can instead shift rapidly and coherently across a neural population, enabling a dynamic transition from detecting a broad category to discriminating individual exemplars. We set out to address a longstanding debate in visual neuroscience about whether the inferotemporal cortex uses a specialized code for specific object categories or a general-purpose code that applies to all objects. We found that face-selective cells in macaque inferotemporal cortex initially adopted a general code optimized for face detection. However, after a rapid concerted population event lasting less than 20 ms, the neural code transformed into a face-specific one, with two striking features: response gradients to principal detection-related dimensions reversed direction, and new tuning emerged for multiple higher-dimensional features that support fine face discrimination. These dynamics in face patches were specific to face stimuli and did not occur in response to non-face objects. Thus, for faces, face cells transition from detection to discrimination by switching from an object-general code to a face-specific one. More broadly, our findings indicate that there is a previously unknown mechanism for neural representation: concerted stimulus-dependent switching of the neural code used by a cortical area.