MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain

Abstract

In vitro studies indicate the neurodevelopmental disorder gene Myelin Transcription Factor 1 Like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L's molecular and cellular functions during differentiation in the mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) but down-regulated upper layer (UL) neuron gene expression, corresponding to an increased ratio of DL/UL neurons in mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets in mouse developing cortex and adult prefrontal cortex (PFC), and to map epigenetic changes due to MYT1L mutation. We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multi-omic dataset integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but does increase H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we show MYT1L interacts with SIN3B and HDAC2 in vivo, providing potential mechanisms underlying any repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights to how MYT1L facilitates neuronal maturation.

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

“…In contrast to our study, Chen et al report an increased Q fraction and a decrease in SOX2+ neural stem cells in Myt1l-deficient mice at E14.5 and suggested MYT1L mainly acts as a transcriptional activator. However, in a recent preprint the same authors found that MYT1L bound and repressed promoters and enhancers of genes involved in early neuronal development programs [71]. Here, using single cell transcriptomics, we show that MYT1L-bound genes are indeed activated in cortical neurons upon loss of MYT1L, supporting its role as a repressor.…”

Asynchronous microexon splicing ofLSD1andPHF21Aduring neurodevelopment

“…MYT1L also represses deeper layer neuron transcriptional program in the adult prefrontal cortex (45) and non-neuronal genes (44,46). SIN3-HDAC is a major corepressor that achieves MYT-mediated transcriptional suppression in vertebrates (45,47).…”

“…Both MYT1 and MYT1L bind to a consensus DNA motif AAAGTTT (25) and transcriptionally suppress the Notch signaling pathway, which negatively regulates neurogenesis and, in turn, promotes neurogenesis (43, 44). MYT1L also represses deeper layer neuron transcriptional program in the adult prefrontal cortex (45) and non-neuronal genes (44, 46). SIN3-HDAC is a major corepressor that achieves MYT-mediated transcriptional suppression in vertebrates (45, 47).…”

“…MYT1L also represses deeper layer neuron transcriptional program in the adult prefrontal cortex (45) and non-neuronal genes (44, 46). SIN3-HDAC is a major corepressor that achieves MYT-mediated transcriptional suppression in vertebrates (45, 47). However, a MYT1 proteomics study with Neuro2A cell identified LSD1-CoREST-PHF21A complex (48), which is consistent with our results and suggests plausible roles of the complex in the MYT-mediated transcriptional regulation of neurodevelopmental gene expression program.…”