Hierarchical Mechanisms for Direct Reprogramming of Fibroblasts to Neurons
Open accessAbstract
Direct lineage reprogramming is a promising approach for human disease modeling and regenerative medicine, with poorly understood mechanisms. Here, we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1, Brn2, and Myt1l. Ascl1 acts as an "on-target" pioneer factor by immediately occupying most cognate genomic sites in fibroblasts. In contrast, Brn2 and Myt1l do not access fibroblast chromatin productively on their own; instead, Ascl1 recruits Brn2 to Ascl1 sites genome wide. A unique trivalent chromatin signature in the host cells predicts the permissiveness for Ascl1 pioneering activity among different cell types. Finally, we identified Zfp238 as a key Ascl1 target gene that can partially substitute for Ascl1 during iN cell reprogramming. Thus, a precise match between pioneer factors and the chromatin context at key target genes is determinative for transdifferentiation to neurons and likely other cell types.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BAZ1B binding regions are enriched for target sites of major regulators of neural crest and its neural derivatives, among which TFAP2A stands out given its core role in neural border formation and neural crest induction and differentiation through binding and stabilization of neural-crest-specific enhancers with NR2F1, NR2F2, and EP300.
“Thus, BAZ1B binding regions are enriched for target sites of major regulators of NC and its neural derivatives (38, 39), among which TFAP2A stands out given its core role in neural border formation and NC induction and differentiation (40) through the binding and stabilization of NC-specific enhancers, in concert with NR2F1, NR2F2, and EP300 (41).”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Liang, Q., Fujita, R., Yamashita, T., Angulo, S. L., Rhinn, H., Rhee, D. B., Doege, C. A., Chau, L., Aubry, L., Vanti, W. B., et al. (2011) · Cell · doi:10.1016/j.cell.2011.07.007 · Cited by 230 · see citing works
RetractedSystematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · see citing works
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386 · see citing works
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108 · see citing works
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,477 · see citing works
MEME SUITE: tools for motif discovery and searching
Bailey, T. L., Boden, M., Buske, F. A., Frith, M., Grant, C. E., Clementi, L., Ren, J., Li, W. W., & Noble, W. S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp335 · Cited by 10,648 · see citing works
Chen, X., Xiu, M., Xing, J., Yu, S., Min, D., & Guo, F. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479439 · Cited by 5,759 · see citing works
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.041 · Cited by 5,361 · see citing works
Self-citationA Third-Generation Lentivirus Vector with a Conditional Packaging System
Dull, T., Zufferey, R., Kelly, M., Mandel, R. J., Nguyen, M., Trono, D., & Naldini, L. (1998) · Journal of Virology · doi:10.1128/jvi.72.11.8463-8471.1998 · Cited by 3,341 · see citing works
Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129 · 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-citationChromHMM: automating chromatin-state discovery and characterization
Ernst, J., & Kellis, M. (2012) · Nature Methods · doi:10.1038/nmeth.1906 · Cited by 2,489 · see citing works
Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors
Ieda, M., Fu, J.-D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B. G., & Srivastava, D. (2010) · Cell · doi:10.1016/j.cell.2010.07.002 · Cited by 2,454 · see citing works
Pioneer transcription factors: establishing competence for gene expression
Zaret, K. S., & Carroll, J. S. (2011) · Genes & Development · doi:10.1101/gad.176826.111 · Cited by 1,589 · see citing works
Proneural genes and the specification of neural cell types
Bertrand, N., Castro, D. S., & Guillemot, F. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn874 · Cited by 1,572 · see citing works
Self-citationStem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming
Jaenisch, R., & Young, R. A. (2008) · Cell · doi:10.1016/j.cell.2008.01.015 · Cited by 1,408 · see citing works
Induction of human neuronal cells by defined transcription factors
Pang, Z. P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D., Yang, T. Q., Citri, A., Sebastiano, V., Marro, S. G., Südhof, T. C., et al. (2011) · Nature · doi:10.1038/nature10202 · Cited by 1,249 · see citing works
Self-citationReversal of Histone Lysine Trimethylation by the JMJD2 Family of Histone Demethylases
Whetstine, J. R., Nottke, A. C., Lan, F., Huarte, M., Smolikov, S., Chen, Z., Spooner, E., Li, E., Zhang, G., Colaiácovo, M. P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.03.028 · Cited by 1,046 · see citing works
Guillemot, F., Lo, L., Johnson, J. E. B., Auerbach, A. B., Anderson, D. J., & Joyner, A. L. (1993) · Cell · doi:10.1016/0092-8674(93)90381-y · Cited by 1,032 · see citing works
Self-citationGiresi, P. G., Kim, J., McDaniell, R. M., Iyer, V. R., & Lieb, J. D. (2006) · Genome Research · doi:10.17615/8cez-3e87 · Cited by 949 · see citing works
Self-citationMicroRNA-mediated conversion of human fibroblasts to neurons
Yoo, A. S., Sun, A. X., Li, L., Shcheglovitov, A., Portmann, T., Li, Y., Lee-Messer, C., Dolmetsch, R. E., Tsien, R. W., & Crabtree, G. R. (2011) · Nature · doi:10.1038/nature10323 · Cited by 919 · see citing works
Forcing cells to change lineages
Graf, T., & Enver, T. (2009) · Nature · doi:10.1038/nature08533 · Cited by 899 · see citing works
Soufi, A., Donahue, G., & Zaret, K. S. (2012) · Cell · doi:10.1016/j.cell.2012.09.045 · Cited by 887 · see citing works
Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors
Huang, P., He, Z., Ji, S., Sun, H., Xiang, D., Liu, C., Hu, Y., Wang, X., & Hui, L. (2011) · Nature · doi:10.1038/nature10116 · Cited by 864 · see citing works
Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem Cell
Conti, L., Pollard, S. M., Gorba, T., Reitano, E., Toselli, M., Biella, G. R., Sun, Y., Sanzone, S., Ying, Q., Cattaneo, E. F., et al. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030283 · Cited by 857 · see citing works
Comprehensive comparative analysis of strand-specific RNA sequencing methods
Levin, J. Z., Yassour, M., Adiconis, X., Nusbaum, C., Thompson, D. A., Friedman, N., Gnirke, A., & Regev, A. (2010) · Nature Methods · doi:10.1038/nmeth.1491 · Cited by 753 · see citing works
Dynamic Regulation of Histone Lysine Methylation by Demethylases
Shi, Y., & Whetstine, J. R. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.12.010 · Cited by 710 · see citing works
Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions
Zentner, G. E., Tesar, P. J., & Scacheri, P. C. (2011) · Genome Research · doi:10.1101/gr.122382.111 · Cited by 564 · see citing works
Ma, Q., Schuurmans, C. J., Guillemot, F., & Anderson, D. J. (1999) · Genes & Development · doi:10.1101/gad.13.13.1717 · Cited by 509 · see citing works
Self-citationBeard, C., Hochedlinger, K., Plath, K., Wutz, A., & Jaenisch, R. (2006) · genesis · doi:10.1002/gene.20180 · Cited by 482 · see citing works
Genome-wide MyoD Binding in Skeletal Muscle Cells: A Potential for Broad Cellular Reprogramming
Cao, Y., Yao, Z., Sarkar, D., Lawrence, M., Sanchez, G. J., Parker, M. H., MacQuarrie, K. L., Davison, J., Morgan, M. T., Ruzzo, W. L., et al. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.02.014 · Cited by 480 · see citing works
Direct Reprogramming of Adult Human Fibroblasts to Functional Neurons under Defined Conditions
Ambasudhan, R., Talantova, M. V., Coleman, R., Xu, Y., Zhu, S., Lipton, S. A., & Ding, S. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.07.002 · Cited by 480 · see citing works
Philip, C. M., Rould, M. A., Weintraub, H. M., & Pabo, C. O. (1994) · Cell · doi:10.1016/0092-8674(94)90159-7 · Cited by 461 · see citing works
Lo, L., Johnson, J. E. B., Wuenschell, C. W., Saito, T., & Anderson, D. J. (1991) · Genes & Development · doi:10.1101/gad.5.9.1524 · Cited by 435 · see citing works
Direct Lineage Conversion of Terminally Differentiated Hepatocytes to Functional Neurons
Marro, S. G., Pang, Z. P., Yang, N., Tsai, M.-C., Qu, K., Chang, H. Y., Südhof, T. C., & Wernig, M. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.09.002 · Cited by 343 · see citing works
Self-citationElmquist, J. K., Breder, C. D., Sherin, J. E., Scammell, T. E., Hickey, W. F., DeWitt, D. L., & Saper, C. B. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970505)381:2 · Cited by 282 · see citing works
Gerber, A. N., Klesert, T. R., Bergstrom, D. A., & Tapscott, S. J. (1997) · Genes & Development · doi:10.1101/gad.11.4.436 · Cited by 262 · see citing works
Direct lineage conversions: unnatural but useful?
Vierbuchen, T., & Wernig, M. (2011) · Nature Biotechnology · doi:10.1038/nbt.1946 · Cited by 259 · see citing works
Self-citationBrn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons
Sugitani, Y., Nakai, S., Minowa, O., Nishi, M., Jishage, K.-I., Kawano, H., Mori, K., Ogawa, M., & Noda, T. (2002) · Genes & Development · doi:10.1101/gad.978002 · Cited by 259 · see citing works
Bellefroid, E., Bourguignon, C., Hollemann, T., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81815-2 · Cited by 233 · see citing works
Dominguez, M. H., Ayoub, A. E., & RAKIC, P. T. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs252 · Cited by 209 · see citing works
Molecular Roadblocks for Cellular Reprogramming
Vierbuchen, T., & Wernig, M. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.09.008 · Cited by 187 · see citing works
Self-citationUsing ChIP-Seq Technology to Generate High-Resolution Profiles of Histone Modifications
O’Geen, H., Echipare, L., & Farnham, P. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-316-5_20 · Cited by 161 · see citing works
Genetic and Epigenetic Determinants of Neurogenesis and Myogenesis
Fong, A. P., Yao, Z., Zhong, J. W., Cao, Y., Ruzzo, W. L., Gentleman, R. C., & Tapscott, S. J. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.01.015 · Cited by 119 · see citing works
Cell-Type-Specific Control of Enhancer Activity by H3K9 Trimethylation
Zhu, Y., van Essen, D., & Saccani, S. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.011 · Cited by 117 · see citing works
Novel Member of the Zinc Finger Superfamily: A C2-HC Finger That Recognizes a Glia-Specific Gene
Kim, J. G., & Hudson, L. D. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.12.5632-5639.1992 · Cited by 117 · see citing works
Nakada, Y., Hunsaker, T., Henke, R. M., & Johnson, J. E. B. (2004) · Development · doi:10.1242/dev.01008 · Cited by 108 · see citing works
Krishnan, S., & Trievel, R. C. (2012) · Structure · doi:10.1016/j.str.2012.10.018 · Cited by 70 · see citing works
Castro, D. S., & Guillemot, F. (2011) · Cell Cycle · doi:10.4161/cc.10.23.18578 · Cited by 58 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
Soufi, A., Garcia, M. F., Jaroszewicz, A., Osman, N., Pellegrini, M., & Zaret, K. S. (2015) · Cell · doi:10.1016/j.cell.2015.03.017 · Cited by 780 · see citing works
Dynamic DNA methylation: In the right place at the right time
Luo, C., Hajkova, P., & Ecker, J. R. (2018) · Science · doi:10.1126/science.aat6806 · Cited by 668 · see citing works
Neurogenesis in the embryonic and adult brain: same regulators, different roles
Urbán, N., & Guillemot, F. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00396 · Cited by 493 · see citing works
Self-citationLoss of p53 drives neuron reprogramming in head and neck cancer
Amit, M., Takahashi, H., Dragomir, M. P., Lindemann, A., Gleber-Netto, F. O., Pickering, C. R., Anfossi, S., Osman, A. A., Cai, Y., Wang, R., et al. (2020) · Nature · doi:10.1038/s41586-020-1996-3 · Cited by 483 · see citing works
Editing the epigenome: technologies for programmable transcription and epigenetic modulation
Thakore, P. I., Black, J. B., Hilton, I. B., & Gersbach, C. A. (2016) · Nature Methods · doi:10.1038/nmeth.3733 · Cited by 451 · see citing works
In Vivo Cellular Reprogramming: The Next Generation
Srivastava, D., & DeWitt, N. (2016) · Cell · doi:10.1016/j.cell.2016.08.055 · Cited by 292 · see citing works
Generation of Human Striatal Neurons by MicroRNA-Dependent Direct Conversion of Fibroblasts
Victor, M. B., Richner, M., Hermanstyne, T. O., Ransdell, J. L., Sobieski, C., Deng, P.-Y., Klyachko, V. A., Nerbonne, J. M., & Yoo, A. S. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.016 · Cited by 295 · see citing works
Abernathy, D. G., Kim, W. K., McCoy, M. J., Lake, A. M., Ouwenga, R., Lee, S. W., Xing, X., Li, D., Lee, H. J., Heuckeroth, R. O., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.08.002 · Cited by 145 · see citing works
Zanella, M., Vitriolo, A., Andirko, A., Martins, P. T., Sturm, S., O’Rourke, T., Laugsch, M., Malerba, N., Skaros, A., Trattaro, S., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw7908 · Cited by 101 · see citing works
Diversity among POU transcription factors in chromatin recognition and cell fate reprogramming
Malik, V., Zimmer, D., & Jauch, R. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2748-5 · Cited by 98 · see citing works
Belinson, H., Nakatani, J., Babineau, B. A., Birnbaum, R. Y., Ellegood, J., Bershteyn, M., McEvilly, R. J., Long, J. M., Willert, K., Klein, O. D., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.207 · Cited by 79 · see citing works
Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons
Luo, C., Lee, Q. Y., Wapinski, O., Castanon, R., Nery, J. R., Mall, M., Kareta, M. S., Cullen, S. M., Goodell, M. A., Chang, H. Y., et al. (2019) · eLife · doi:10.7554/elife.40197 · Cited by 76 · see citing works
Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs
Cates, K., McCoy, M. J., Kwon, J.-S., Liu, Y., Abernathy, D. G., Zhang, B., Liu, S., Gontarz, P., Kim, W. K., Chen, S., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2020.08.015 · Cited by 67 · see citing works
Herdy, J., Schafer, S., Kim, Y., Ansari, Z., Zangwill, D., Ku, M., Paquola, A., Lee, H., Mertens, J., & Gage, F. H. (2019) · eLife · doi:10.7554/elife.41356 · Cited by 64 · see citing works
Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes
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., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0490-3 · Cited by 50 · see citing works
Self-citationFuglerud, B. M., Lemma, R. B., Wanichawan, P., Sundaram, A. Y. M., Eskeland, R., & Gabrielsen, O. S. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx364 · Cited by 36 · see citing works
Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Katsuda, T., Sussman, J. H., Ito, K., Katznelson, A., Yuan, S., Takenaka, N., Li, J., Merrell, A. J., Cure, H., Li, Q., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45939-z · Cited by 33 · see citing works
Canalizing cell fate by transcriptional repression
Lim, B., Domsch, K., Mall, M., & Lohmann, I. (2024) · Molecular Systems Biology · doi:10.1038/s44320-024-00014-z · Cited by 19 · see citing works
- Authors
- Wapinski, O. L., Vierbuchen, T., Qu, K., Lee, Q. Y., Chanda, S., Fuentes, D. R., Giresi, P. G., Ng, Y. H., Marro, S., Neff, N. F., Drechsel, D., Martynoga, B., Castro, D. S., Webb, A. E., Südhof, T. C., Brunet, A., Guillemot, F., Chang, H. Y., & Wernig, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Stanford Medicine (US)
- Stanford University (US)
- National Institute for Medical Research (GB)
- Instituto Gulbenkian de Ciência (PT)
- Corresponding author
- Chang, Howard Y.
- Wernig, Marius
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 155
- Issue
- 3
- Pages
- 621-635
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3871197
- OpenAlex
- W2068478010
- Cited by
- 627
- References
- 50
- Citations by year
- 2026: 27 · 2025: 33 · 2024: 39 · 2023: 54 · 2022: 46 · 2021: 62 · 2020: 55 · 2019: 62 · 2018: 55 · 2017: 53 · 2016: 54 · 2015: 51 · 2014: 33 · 2013: 3
- FWCI
- 21.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG036695)
- National Cancer Institute (T32CA009302)
- 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
- fibroblast-to-neuron conversion, ASCL1, Brn2, MYT1L, pioneer transcription factors, chromatin accessibility, chromatin signatures, transdifferentiation, transcriptional hierarchy
- MeSH terms
- Animals, Cell Differentiation, Chromatin, Embryo, Mammalian, Fibroblasts, Humans, Nerve Tissue Proteins, Neurons, Repressor Proteins, Transcription Factors, POU Domain Factors, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Gene Regulatory Networks, Genome-Wide Association Study, Cellular Reprogramming
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
