Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates
Open accessAbstract
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, by studying the reprogramming of mouse fibroblasts to neurons, 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 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.
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14 candidates were reported to promote the predicted cell fate.
“14 were reported to promote the predicted cell fate, including the neuronal safeguard MYT1L12”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [12]
The neuron-specific repressor MYT1L suppresses non-neuronal genes in neurons.
“Similarly, the neuron-specific repressor MYT1L suppresses non-neuronal genes in neurons11,12.”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [12]
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437 · see citing works
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556 · see citing works
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
Direct conversion of fibroblasts to functional neurons by defined factors
Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Südhof, T. C., & Wernig, M. (2010) · Nature · doi:10.1038/nature08797 · Cited by 3,017 · see citing works
Self-citationSynaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
Flagged first, then by citations
Research works printed but not linked: 23
- [1]Schäfer BW, Blakely BT, Darlington GJ & Blau HM Effect of cell history on response to helix-loop-helix family of myogenic regulators. Nature 344, 454– 458 (1990). 2157160
- [2]Terranova R, Pereira CF, Roure, Du, C., Merkenschlager, M. & Fisher, A. G. Acquisition and extinction of gene expression programs are separable events in heterokaryon reprogramming. J Cell Sci 119, 2065– 2072 (2006). 16638804
- [3]Xu J, Du Y & Deng H Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell 16, 119– 134 (2015). 25658369
- [4]Santisteban P, Recacha P, Metzger DE & Zaret KS Dynamic expression of groucho-related genes Grg1and Grg3in foregut endoderm and antagonism of differentiation. Dev Dyn 239, 980– 986 (2010). 20108349 PMC3071952
- [5]Schoenherr CJ & Anderson DJ The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360– 1363 (1995). 7871435
- [6]Matsushita F, Kameyama T, Kadokawa Y & Marunouchi T Spatiotemporal expression pattern of Myt/NZF family zinc finger transcription factors during mouse nervous system development. Dev Dyn 243, 588– 600 (2014). 24214099
- [7]Masserdotti G, Gascón S & Götz M Direct neuronal reprogramming: learning from and for development. Development 143, 2494– 2510 (2016). 27436039
- [8]Wapinski OL Hierarchical Mechanisms for Direct Reprogramming of Fibroblasts to Neurons. Cell 155, 621– 635 (2013). 24243019 PMC3871197
- [10]Chanda S Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Reports 3, 282– 296 (2014). 25254342 PMC4176533
- [11]Jiang Y A novel family of Cys-Cys, His-Cys zinc finger transcription factors expressed in developing nervous system and pituitary gland. J Biol Chem 271, 10723– 10730 (1996). 8631881
- [12]Yee KS & Yu VC Isolation and characterization of a novel member of the neural zinc finger factor/myelin transcription factor family with transcriptional repression activity. J Biol Chem 273, 5366– 5374 (1998). 9478997
- [13]Besold AN, Oluyadi AA & Michel SLJ Switching Metal Ion Coordination and DNA Recognition in a Tandem CCHHC-type Zinc Finger Peptide. Inorg. Chem 52, 4721– 4728 (2013). 23521535 PMC3671583
- [14]Romm E, Nielsen JA, Kim JG & Hudson LD Myt1 family recruits histone deacetylase to regulate neural transcription. Journal of Neurochemistry 93, 1444– 1453 (2005). 15935060 PMC1201409
- [15]Spronk CA The Mad1-Sin3B interaction involves a novel helical fold. Nat. Struct. Biol 7, 1100– 1104 (2000). 11101889
- [16]Grzenda A, Lomberk G, Zhang J-S & Urrutia R Sin3: master scaffold and transcriptional corepressor. Biochim Biophys Acta 1789, 443– 450 (2009). 19505602 PMC3686104
- [17]Vasconcelos FF MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis. Cell Reports 17, 469– 483 (2016). 27705795 PMC5067283
- [18]Bellefroid EJ X-MyT1, a Xenopus C2HC-type zinc finger protein with a regulatory function in neuronal differentiation. Cell 87, 1191– 1202 (1996). 8980226
- [19]Kageyama R, Ohtsuka T, Shimojo H & Imayoshi I Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat. Neurosci 11, 1247– 1251 (2008). 18956012
- [20]Axelrod JD Delivering the lateral inhibition punchline: it’s all about the timing. Science Signaling 3, pe38– pe38 (2010). 20978236
- [21]De Rocker N Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity. Genet. Med 17, 460– 466 (2015). 25232846
- [23]Lee Y Microduplications disrupting the MYT1L gene (2p25.3) are associated with schizophrenia. Psychiatr. Genet 22, 206– 209 (2012). 22547139 PMC3384746
- [24]Li W Association study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population. Genes Brain Behav. 11, 87– 93 (2012). 21923761
- [25]Teif VB Genome-wide nucleosome positioning during embryonic stem cell development. Nat Struct Mol Biol 19, 1185– 1192 (2012). 23085715
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Self-citationShi, Y., Shao, Q., Li, Z., Gonzalez, G. A., Lu, F., Wang, D., Pu, Y., Huang, A., Zhao, C., He, C., et al. (2018) · Neuroscience Bulletin · doi:10.1007/s12264-018-0207-9 · Cited by 34 · see citing works
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Self-citationMansfield, P., Constantino, J. N., & Baldridge, D. (2020) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32781 · Cited by 27 · see citing works
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Self-citationLim, B., Kamal, A., Gomez Ramos, B., Adrian Segarra, J. M., Ibarra, I. L., Dignas, L., Kindinger, T., Volz, K., Rahbari, M., Rahbari, N., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02081-w · Cited by 17 · see citing works
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- Authors
- Mall, M., Kareta, M. S., Chanda, S., Ahlenius, H., Perotti, N., Zhou, B., Grieder, S. D., Ge, X., Drake, S., Euong Ang, C., Walker, B. M., Vierbuchen, T., Fuentes, D. R., Brennecke, P., Nitta, K. R., Jolma, A., Steinmetz, L. M., Taipale, J., Südhof, T. C., & Wernig, M.
- Affiliations
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Howard Hughes Medical Institute (US)
- Lund University (SE)
- Stanford University (US)
- Karolinska Institutet (SE)
- European Molecular Biology Laboratory (DE)
- University of Helsinki (FI)
- Corresponding author
- Wernig, Marius
- ORCID
- Venue
- Nature
- Published
- 2017-04-05
- Volume
- 544
- Issue
- 7649
- Pages
- 245-249
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11348803
- OpenAlex
- W2604658068
- Cited by
- 225
- References
- 6
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 23 · 2023: 22 · 2022: 20 · 2021: 34 · 2020: 28 · 2019: 25 · 2018: 18 · 2017: 11
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-06-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (R01MH092931)
- National Cancer Institute (T32CA009151)
- National Institute of Neurological Disorders and Stroke (RC4NS073015)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- MYT1L, neuronal identity, lineage reprogramming, fibroblast-to-neuron conversion, SIN3B, Notch signaling, Hes1, open chromatin, epigenetic silencing, neurogenesis, rest, Groucho, transcriptional repression, neuronal differentiation, postmitotic neurons, mouse brain development, chromatin accessibility
- MeSH terms
- Transcription Factor HES-1, Protein Domains, Animals, Animals, Newborn, Brain, Cells, Cultured, Chromatin, Fibroblasts, Humans, Nerve Tissue Proteins, Neurons, Organ Specificity, Repressor Proteins, Transcription Factors, Signal Transduction, Cell Lineage, Gene Silencing, Mice, Receptors, Notch, Neurogenesis, Cellular Reprogramming
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