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Differentiation of a Human Neural Stem Cell Line on Three Dimensional Cultures, Analysis of MicroRNA and Putative Target Genes
Published on: April 12, 2015
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DOT1L activity affects neural stem cell division mode and reduces differentiation and ASNS expression.
Bismark Appiah1,2, Camila L Fullio1,2, Chiara Ossola3
1Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
EMBO Reports
|June 29, 2023
Summary
Histone methyltransferase DOT1L regulates brain development by controlling progenitor cell division. Inhibiting DOT1L promotes neurogenesis through metabolic gene regulation and ASNS expression, impacting apical progenitor lineage progression.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Biology
Background:
- Cortical neurogenesis relies on apical progenitors (APs) balancing self-renewal and differentiation.
- Epigenetic mechanisms are crucial for regulating AP division modes.
Purpose of the Study:
- To investigate the role of histone methyltransferase DOT1L in the epigenetic control of AP division.
- To elucidate how DOT1L enzymatic activity influences neurogenesis and AP lineage progression.
Main Methods:
- Lineage tracing combined with single-cell RNA sequencing of clonally related cells.
- Analysis of DOT1L inhibition effects on AP division modes and gene expression.
- Investigating the interplay between DOT1L, EZH2/PRC2 pathway, and asparagine synthetase (ASNS).
Main Results:
- DOT1L inhibition shifts APs from asymmetric self-renewal to symmetric neurogenic divisions, increasing neurogenesis.
- DOT1L activity suppresses AP differentiation by promoting metabolic gene transcription.
- DOT1L inhibition reduces EZH2/PRC2 pathway activity, leading to increased ASNS expression.
- ASNS overexpression mimics DOT1L inhibition effects on APs and neuronal differentiation.
Conclusions:
- DOT1L epigenetic regulation is critical for controlling AP lineage progression during cortical development.
- Crosstalk between DOT1L activity and the PRC2 pathway regulates asparagine metabolism and AP fate.
- ASNS acts as a key mediator in DOT1L-controlled neurogenesis.
