Pluto Bioinformatics

GSE72121: The neuron-specific transcription factor Myt1l represses many non-neuronal fates

Bulk RNA sequencing

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. SOURCE: Marius Wernig Stanford University