A transcription regulator atlas identifies TOX3 as an Atoh1 co-activator in cerebellar development and tumorigenesis

Mechanistically, how lineage-defining factors such as Atoh1 drive robust gene expression despite weak intrinsic transactivation activity remains unclear. We show that Tox3 physically associates with Atoh1 and co-occupies shared regulatory elements, converting an otherwise weak single-copy Atoh1-reponsive E-box into a highly active enhancer that drives transcriptional activation by up to 120-fold, including at an ultra-conserved E-box downstream of Atoh1 itself.

Cross-species single-cell comparisons further show an association between Tox3 expression and cerebellum expansion during vertebrate evolution. Together, this work supports Tox3 as a critical Atoh1 co-activator in cerebellar development, tumorigenesis and evolution, while providing an atlas and screening strategy as a valuable resource for exploring novel transcriptional regulators in organogenesis and tissue physiology.