EMBO reports · 2023
DOT1L activity affects neural stem cell division mode and reduces differentiation and ASNS expression.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Appiah Bismark, Fullio Camila L, Ossola Chiara, Bertani Ilaria, Restelli Elena, Cheffer Arquimedes, Polenghi Martina, Haffner Christiane, Garcia-Miralles Marta, Zeis Patrice, Treppner Martin, Bovio Patrick, Schlichtholz Laura, Mas-Sanchez Aina, Zografidou Lea, Winter Jennifer, Binder Harald, Grün Dominic, Kalebic Nereo, Taverna Elena, Vogel Tanja
Аннотация
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.