Single-locus chromatin memory enables flexible spatial fate specification in the Drosophila visual system

Abstract

Spatial patterning generates neuronal diversity by compartmentalizing progenitors into domains with distinct molecular identities. However, these patterning cues are often transient in neurogenic domains, raising the question of how spatial information can be preserved and how rigidly it constrains neuronal fates. Here we show that a single-locus chromatin memory in the Drosophila medulla enables spatial identity to be both faithfully executed and flexibly bypassed. Medulla progenitors are partitioned into three spatial domains marked by Vsx1, Optix and Bifid. Domain-resolved single-cell multiome profiling reveals that progenies from different neuroepithelial domains are nearly indistinguishable for both transcriptome and chromatin accessibility, although persistent, domain-specific accessibility is retained only at a single spatial-factor locus, either Vsx1/2 or Bifid. These same factors are absent when neuroepithelial cells are converted to neural stem cells but are re-expressed in postmitotic neurons to execute domain-specific fates. Because this bookmarking is so restricted, specific classes of neurons can skip the domain-specific re-expression program and default to a common ground state, adopting equivalent fates regardless of spatial origin. Other neurons reach the same domain-ignoring state by expressing Vsx1/2 through a program independent of their domain of origin. PRC2-mediated silencing restricts Vsx1 re-expression to its home domain, while temporal identity and Notch signaling in newborn neurons determine which neurons engage or bypass the spatial program. Thus, single-locus chromatin memory preserves spatial information without making it an obligatory determinant of every neuronal fate.