- Awarded: 2017
- Award Type: Research
- Award #: 514519
Myt1-like (Myt1l) is a zinc finger transcription factor that has a unique expression pattern: it is both highly specific for and is expressed in virtually all neurons. Marius Wernig and Thomas Südhof found that Myt1l is one of three powerful factors that are able to directly reprogram fibroblasts to functional neurons1. Recently, the human MYT1L gene was found to be mutated in families with autism spectrum disorder and other neurodevelopmental disorders. Despite its importance for these conditions, little is known about Myt1l’s function, and no mouse knock-out model has been reported to date. To better characterize Myt1, Wernig and Südhof have begun to investigate its molecular role during in vitro reprogramming.
Wernig and Südhof have found that Myt1l acts primarily as a transcriptional repressor in reprogramming and silencing fibroblast genes together with multiple members of the Notch pathway. Chromatin-immunoprecipitation followed by ChIP-sequencing (ChIP-Seq) showed that Myt1l binds mostly non-neuronal genes and that its binding pattern is similar in fibroblasts and neurons, despite their vastly different transcriptome. Assessment of nucleosomal positioning revealed that Myt1l targets are in accessible chromatin in fibroblasts. They now propose to investigate whether Myt1l blocks the Notch pathway during normal neurogenesis.
It is well established that the Notch pathway is activated by Delta in neighboring cells to block neuronal differentiation, nicely explaining how the progenitor cell pool is maintained. However, it is completely unclear how the differentiating cells themselves can escape Notch activation. The hypothesized transcriptional silencing of downstream Notch effectors by Myt1l as suggested by ChIP-Seq would provide a simple molecular solution for this conundrum. Wernig and Südhof then plan to follow up their observation that Myt1l represses the fibroblast program during neuronal reprogramming and binds many non-neuronal genes by ChIP-Seq in neurons. To this end, they will test whether Myt1l plays a role in maintaining neuronal identity by suppressing many non-neuronal fates. If this hypothesis were to be confirmed, Myt1l would have the exact opposite function of the repressor REST, which is known to suppress the neuronal lineage in many non-neuronal cells.