Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates

• Published in: Nature (London) Vol. 544; no. 7649; pp. 245 - 249
• Main Authors: Mall, Moritz, Kareta, Michael S., Chanda, Soham, Ahlenius, Henrik, Perotti, Nicholas, Zhou, Bo, Grieder, Sarah D., Ge, Xuecai, Drake, Sienna, Euong Ang, Cheen, Walker, Brandon M., Vierbuchen, Thomas, Fuentes, Daniel R., Brennecke, Philip, Nitta, Kazuhiro R., Jolma, Arttu, Steinmetz, Lars M., Taipale, Jussi, Südhof, Thomas C., Wernig, Marius
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.04.2017; Nature Publishing Group
• Subjects: 13/106; 38/1; 38/22; 38/23; 38/39; 45/90; 631/136/2435; 631/378/340; 9/74; Animals; Animals, Newborn; Basic Medicine; Binding sites; Brain - cytology; Brain - embryology; Brain - metabolism; Cell Lineage - genetics; Cells, Cultured; Cellular Reprogramming - genetics; Chromatin - genetics; Chromatin - metabolism; Deoxyribonucleic acid; DNA; Fibroblasts; Fibroblasts - cytology; Fibroblasts - metabolism; Gene expression; Gene Silencing; Growth factors; Humanities and Social Sciences; Humans; letter; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; multidisciplinary; Mutation; Myelin proteins; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - metabolism; Neurogenesis - genetics; Neurons; Neurons - cytology; Neurons - metabolism; Neurosciences; Neurovetenskaper; Ontology; Organ Specificity - genetics; Physiology; Protein Domains; Protein research; Proteins; Receptors, Notch - deficiency; Repressor Proteins - chemistry; Repressor Proteins - deficiency; Repressor Proteins - metabolism; Science; Signal Transduction; Studies; Transcription (Genetics); Transcription Factor HES-1 - deficiency; Transcription factors; Transcription Factors - deficiency; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature21722

The neuron-specific transcription factor Myt1l represses many somatic lineage programs, but not the neuronal lineage program, to both induce and maintain neuronal identity. Myt1L represses non-neuronal fates Lineage reprogramming by expression of transcription factors that modulate target cell fate program requires gene expression of the donor cell to be silenced. Given our current knowledge, we would expect that each reprogramming cocktail would need to differ for distinct cells of origin, but intriguingly this has not been the case experimentally so far. Marius Wernig and colleagues have found that the neuronal reprogramming factor Myt1l, which is expressed in all neurons, promotes neuronal fate in mice by repressing all other lineages during reprogramming from other cell types as well as during neurogenesis and in primary neurons. Their data suggests that changing epigenetic marks would not be sufficient to maintain a particular cell fate, and alternative lineages are actively repressed to confer neuronal identity. Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs 1 , 2 . In reprogramming, the same factors are often used to reprogram many different donor cell types 3 . As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors 4 , 5 , 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, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) 6 exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via 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 knockdown 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.