All Publications

  • Insights and applications of direct neuronal reprogramming. Current opinion in genetics & development Schaukowitch, K., Janas, J. A., Wernig, M. 2023; 83: 102128


    Direct neuronal reprogramming converts somatic cells of a defined lineage into induced neuronal cells without going through a pluripotent intermediate. This approach not only provides access to the otherwise largely inaccessible cells of the brain for neuronal disease modeling, but also holds great promise for ultimately enabling neuronal cell replacement without the use of transplantation. To improve efficiency and specificity of direct neuronal reprogramming, much of the current efforts aim to understand the mechanisms that safeguard cell identities and how the reprogramming cells overcome the barriers resisting fate changes. Here, we review recent discoveries into the mechanisms by which the donor cell program is silenced, and new cell identities are established. We also discuss advancements that have been made toward fine-tuning the output of these reprogramming systems to generate specific types of neuronal cells. Finally, we highlight the benefit of using direct neuronal reprogramming to study age-related disorders and the potential of in vivo direct reprogramming in regenerative medicine.

    View details for DOI 10.1016/j.gde.2023.102128

    View details for PubMedID 37862835

  • Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation. Molecular cell Janas, J. A., Zhang, L., Luu, J. H., Demeter, J., Meng, L., Marro, S. G., Mall, M., Mooney, N. A., Schaukowitch, K., Ng, Y. H., Yang, N., Huang, Y., Neumayer, G., Gozani, O., Elias, J. E., Jackson, P. K., Wernig, M. 2022


    Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce and maintain appropriate lineage-specific gene expression remain elusive. Here, we used an unbiased proteomics approach to characterize chromatin regulators that mediate the induction of neuronal cell fate. We found that Tip60 acetyltransferase is essential to establish neuronal cell identity partly via acetylation of the histone variant H2A.Z. Despite its tight correlation with gene expression and active chromatin, loss of H2A.Z acetylation had little effect on chromatin accessibility or transcription. Instead, loss of Tip60 and acetyl-H2A.Z interfered with H3K4me3 deposition and activation of a unique subset of silent, lineage-restricted genes characterized by a bivalent chromatin configuration at their promoters. Altogether, our results illuminate the mechanisms underlying bivalent chromatin activation and reveal that H2A.Z acetylation regulates neuronal fate specification by establishing epigenetic competence for bivalent gene activation and cell lineage transition.

    View details for DOI 10.1016/j.molcel.2022.11.002

    View details for PubMedID 36417913

  • Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes. Nature cell biology Lee, Q. Y., Mall, M., Chanda, S., Zhou, B., Sharma, K. S., Schaukowitch, K., Adrian-Segarra, J. M., Grieder, S. D., Kareta, M. S., Wapinski, O. L., Ang, C. E., Li, R., Sudhof, T. C., Chang, H. Y., Wernig, M. 2020


    The on-target pioneer factors Ascl1 and Myod1 are sequence-related but induce two developmentally unrelated lineages-that is, neuronal and muscle identities, respectively. It is unclear how these two basic helix-loop-helix (bHLH) factors mediate such fundamentally different outcomes. The chromatin binding of Ascl1 and Myod1 was surprisingly similar in fibroblasts, yet their transcriptional outputs were drastically different. We found that quantitative binding differences explained differential chromatin remodelling and gene activation. Although strong Ascl1 binding was exclusively associated with bHLH motifs, strong Myod1-binding sites were co-enriched with non-bHLH motifs, possibly explaining why Ascl1 is less context dependent. Finally, we observed that promiscuous binding of Myod1 to neuronal targets results in neuronal reprogramming when the muscle program is inhibited by Myt1l. Our findings suggest that chromatin access of on-target pioneer factors is primarily driven by the protein-DNA interaction, unlike ordinary context-dependent transcription factors, and that promiscuous transcription factor binding requires specific silencing mechanisms to ensure lineage fidelity.

    View details for DOI 10.1038/s41556-020-0490-3

    View details for PubMedID 32231311