RT Journal Article
SR Electronic
T1 DOT1L activity affects cell lineage progression in the developing brain by controlling metabolic programs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.08.487591
DO 10.1101/2022.04.08.487591
A1 Bismark Appiah
A1 Camilla L. Fullio
A1 Christiane Haffner
A1 Patrice Zeis
A1 Martin Treppner
A1 Patrick Bovio
A1 Arquimedes Cheffer
A1 Ilaria Bertani
A1 Harald Binder
A1 Dominic Grün
A1 Nereo Kalebic
A1 Elena Taverna
A1 Tanja Vogel
YR 2022
UL http://biorxiv.org/content/early/2022/04/12/2022.04.08.487591.abstract
AB Cortical neurogenesis depends on the tight balance between self-renewal and differentiation of apical progenitors (APs), the key progenitor type generating all other neural cells including neocortical neurons. We here report the activity of the histone methyltransferase DOT1L as a gatekeeper for AP cell identity. Combining lineage tracing with single-cell RNA sequencing of clonally related cells, we explore consequences of DOT1L inhibition on AP lineage progression during neurogenesis in the embryonic mouse neocortex. At the cellular level, DOT1L inhibition led to increased neurogenesis driven by a shift from asymmetric self-renewing to symmetric neurogenic divisions of APs. At the molecular level, we show that DOT1L activity preserved AP identity by promoting transcription of a gene set involved in AP metabolism. On a mechanistic level, DOT1L inhibition increased expression of metabolic genes, including microcephaly-associated Asparagine synthetase (Asns) and overexpression of ASNS in APs resulted in increased neuronal differentiation. Asns expression was predicted to be controlled through EZH2 and we show that DOT1L activity allows PRC2-mediated repression of Asns expression. Importantly, inhibition of ASNS activity rescued increased AP differentiation upon DOT1L inhibition. Our data show that DOT1L activity/PRC2 crosstalk controls AP lineage progression by regulating AP metabolism, and they provide a mechanistic view on how DOT1L activity might affect neocortical neurogenesis.Competing Interest StatementThe authors have declared no competing interest.