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MYT1L deficiency impairs excitatory neuron trajectory during cortical development [P21]

ABSTRACT: MYT1L is a neuron-specific transcription factor routinely used in fibroblast-to-neuron transdifferentiation. Furthermore, mutations that reduce MYT1L function are associated with autism. Likewise, MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss, and the cumulative impact of haploinsufficiency on chromatin has been unclear. In this study, we profiled 277,698 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete. We found that MYT1L deficiency had the strongest impact on deep layer excitatory neurons, specifically disrupting their trajectory of development and preventing arrival at a mature state. We also demonstrated that MYT1L acts primarily, but not exclusively, as a transcriptional repressor in these cell types, and most effects on gene expression are cell-autonomous. Furthermore, we developed and applied single-nucleus combinatorial indexing Calling Cards (sci-CC), an exponentially scalable method to simultaneously record gene expression and longitudinal enhancer activity in single nuclei over time. We find that the disruptions persist throughout neurodevelopment as excitatory neurons were disproportionately affected. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE262366 | GEO | 2024/04/11

REPOSITORIES: GEO

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Project description:Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs but not the neuronal program during reprogramming and neurogenesis and in primary mouse neurons. The repressive function of Myt1l is mediated by recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knock-down of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar ‘many-but-one’ lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

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MYT1L deficiency impairs excitatory neuron trajectory during cortical development [P21]

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