Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila

Elizabeth D Larson,Hideyuki Komori,Cheng-Yu Lee,Cyrina M Ostgaard,Tyler J Gibson,Danielle C Hamm,Melissa M Harrison,Jack M Schnell

doi:10.1038/s41467-021-27506-y

Abstract

During Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cis-regulatory regions and in doing so reprograms the zygotic transcriptome. While Zelda is essential later in development, it is unclear how the ability of Zelda to define cis-regulatory regions is shaped by cell-type-specific chromatin architecture. Asymmetric division of neural stem cells (neuroblasts) in the fly brain provide an excellent paradigm for investigating the cell-type-specific functions of this pioneer factor. We show that Zelda synergistically functions with Notch to maintain neuroblasts in an undifferentiated state. Zelda misexpression reprograms progenitor cells to neuroblasts, but this capacity is limited by transcriptional repressors critical for progenitor commitment. Zelda genomic occupancy in neuroblasts is reorganized as compared to the embryo, and this reorganization is correlated with differences in chromatin accessibility and cofactor availability. We propose that Zelda regulates essential transitions in the neuroblasts and embryo through a shared gene-regulatory network driven by cell-type-specific enhancers.

Highlights

During Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cisregulatory regions and in doing so reprograms the zygotic transcriptome
While type I neuroblasts directly contribute to neurogenesis, type II neuroblasts divide asymmetrically to self-renew and to generate a sibling cell that commits to an intermediate neural progenitor (INP) identity and functions as a transit-amplifying cell
Despite Dpn expression and the capacity to undergo a limited number of asymmetric divisions, INPs lack the functional characteristics of the type II neuroblast from which they are derived

Summary

Introduction

During Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cisregulatory regions and in doing so reprograms the zygotic transcriptome. While it is possible that the reprogramming function of Zld requires these distinctive properties of early development, Zld is necessary for development after the MZT26 It remains unclear whether Zld defines cis-regulatory regions in tissues outside the early embryo and if so, how this activity is regulated by the cell-type-specific chromatin established during development. Despite Dpn expression and the capacity to undergo a limited number of asymmetric divisions, INPs lack the functional characteristics of the type II neuroblast from which they are derived These molecularly defined intermediate stages of INP commitment provide a powerful system to investigate the temporal control of enhancer activity as stem cells exit the undifferentiated state

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Results

Conclusion