DOT1L activity affects neural stem cell division mode and reduces differentiation and ASNS expression

Abstract

Cortical neurogenesis depends on the balance between self‐renewal and differentiation of apical progenitors (APs). Here, we study the epigenetic control of AP's division mode by focusing on the enzymatic activity of the histone methyltransferase DOT1L. Combining lineage tracing with single‐cell RNA sequencing of clonally related cells, we show at the cellular level that DOT1L inhibition increases neurogenesis driven by a shift of APs from asymmetric self‐renewing to symmetric neurogenic consumptive divisions. At the molecular level, DOT1L activity prevents AP differentiation by promoting transcription of metabolic genes. Mechanistically, DOT1L inhibition reduces activity of an EZH2/PRC2 pathway, converging on increased expression of asparagine synthetase (ASNS), a microcephaly associated gene. Overexpression of ASNS in APs phenocopies DOT1L inhibition, and also increases neuronal differentiation of APs. Our data suggest that DOT1L activity/PRC2 crosstalk controls AP lineage progression by regulating asparagine metabolism. image The epigenetic modifier DOT1L represses expression of asparagine synthetase to preserve the apical progenitor state and prevents microcephaly by premature neuronal differentiation. DOT1L influences the balance between symmetric and asymmetric cell divisions. DOT1L prevents expression of ASNS in apical progenitors in concert with PRC2. DOT1L regulates apical progenitor metabolism.