A Systematic Approach to Identify Candidate Transcription Factors that Control Cell Identity
Open accessAbstract
Hundreds of transcription factors (TFs) are expressed in each cell type, but cell identity can be induced through the activity of just a small number of core TFs. Systematic identification of these core TFs for a wide variety of cell types is currently lacking and would establish a foundation for understanding the transcriptional control of cell identity in development, disease, and cell-based therapy. Here, we describe a computational approach that generates an atlas of candidate core TFs for a broad spectrum of human cells. The potential impact of the atlas was demonstrated via cellular reprogramming efforts where candidate core TFs proved capable of converting human fibroblasts to retinal pigment epithelial-like cells. These results suggest that candidate core TFs from the atlas will prove a useful starting point for studying transcriptional control of cell identity and reprogramming in many human 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?
The hepatocyte core transcriptional regulatory circuitry comprises 13 Hep-ID transcription factors commonly defined in different studies as interconnected hepatocyte-specific transcription factors.
“We defined the hepatocyte CoRC as a set of 13 Hep‐ID TFs commonly defined in different studies as interconnected hepatocyte‐specific TFs (Kyrmizi et al, 2006; D'Alessio Ana et al, 2015; Zhou et al, 2017; Dubois et al, 2020a; Dataset EV1).”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as D'Alessio Ana et al, 2015
The Results (page unavailable) say the atlas includes candidate core transcription factors for hepatocytes, with overlap with factors used in hepatocyte reprogramming. The paper does not define a 13-factor Hep-ID set or establish that those factors form an interconnected hepatocyte-specific circuitry; it focuses on the ten top-scoring factors per cell type as primary candidates. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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
Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
Maurano, M. T., Humbert, R., Rynes, E., Thurman, R. E., Haugen, E., Wang, H., Reynolds, A. P., Sandstrom, R., Qu, H., Brody, J., et al. (2012) · Science · doi:10.1126/science.1222794 · Cited by 3,716 · see citing works
Super-enhancers in the control of cell identity and disease
Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-André, V., Sigova, A. A., Hoke, H. A., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.09.053 · Cited by 3,662 · see citing works
Self-citationDirect 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
A census of human transcription factors: function, expression and evolution
Vaquerizas, J. M., Kummerfeld, S. K., Teichmann, S. A., & Luscombe, N. M. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2538 · Cited by 1,573 · see citing works
The retinal pigment epithelium: a versatile partner in vision
Bok, D. (1993) · Journal of Cell Science · doi:10.1242/jcs.1993.supplement_17.27 · Cited by 593 · see citing works
H3K4me3 breadth is linked to cell identity and transcriptional consistency
Benayoun, B. A., Pollina, E. A., Ucar, D., Mahmoudi, S., Karra, K., Wong, E. D., Devarajan, K., Daugherty, A. C., Kundaje, A. B., Mancini, E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.027 · Cited by 536 · see citing works
Idelson, M., Alper, R., Obolensky, A., Ben-Shushan, E., Hemo, I., Yachimovich-Cohen, N., Khaner, H., Smith, Y., Wiser, O., Gropp, M., et al. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.07.002 · Cited by 486 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 47
- Breitling R. Armengaud P. Amtmann A. Herzyk P. Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments FEBS Lett. 573 2004 83 92 15327980
- Buganim Y. Itskovich E. Hu Y.C. Cheng A.W. Ganz K. Sarkar S. Fu D. Welstead G.G. Page D.C. Jaenisch R. Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors Cell Stem Cell 11 2012 373 386 22958931 PMC3438668
- Buganim Y. Faddah D.A. Jaenisch R. Mechanisms and models of somatic cell reprogramming Nat. Rev. Genet. 14 2013 427 439 23681063 PMC4060150
- Cabili M.N. Trapnell C. Goff L. Koziol M. Tazon-Vega B. Regev A. Rinn J.L. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses Genes Dev. 25 2011 1915 1927 21890647 PMC3185964
- Cahan P. Li H. Morris S.A. Lummertz da Rocha E. Daley G.Q. Collins J.J. CellNet: network biology applied to stem cell engineering Cell 158 2014 903 915 25126793 PMC4233680
- Cyranoski D. Stem cells cruise to clinic Nature 494 2013 413 23446394
- Cyranoski D. Stem-cell method faces fresh questions Nature 507 2014 283 24646974
- Davis F.P. Eddy S.R. Transcription factors that convert adult cell identity are differentially polycomb repressed PLoS ONE 8 2013 e63407 23650565 PMC3641127
- Farh K.K. Marson A. Zhu J. Kleinewietfeld M. Housley W.J. Beik S. Shoresh N. Whitton H. Ryan R.J. Shishkin A.A. Genetic and epigenetic fine mapping of causal autoimmune disease variants Nature 518 2015 337 343 25363779 PMC4336207
- Ford K.M. Saint-Geniez M. Walshe T. Zahr A. D’Amore P.A. Expression and role of VEGF in the adult retinal pigment epithelium Invest. Ophthalmol. Vis. Sci. 52 2011 9478 9487 22058334 PMC3250352
- Fuglede B. Topsoe F. Jensen-Shannon Divergence and Hilbert space embedding. Proceedings of the 2004 International Symposium on Information Theory 2004 IEEE p. 31
- Graf T. Historical origins of transdifferentiation and reprogramming Cell Stem Cell 9 2011 504 516 22136926
- Graf T. Enver T. Forcing cells to change lineages Nature 462 2009 587 594 19956253
- Heinäniemi M. Nykter M. Kramer R. Wienecke-Baldacchino A. Sinkkonen L. Zhou J.X. Kreisberg R. Kauffman S.A. Huang S. Shmulevich I. Gene-pair expression signatures reveal lineage control Nat. Methods 10 2013 577 583 23603899 PMC4131748
- Henriques T. Gilchrist D.A. Nechaev S. Bern M. Muse G.W. Burkholder A. Fargo D.C. Adelman K. Stable pausing by RNA polymerase II provides an opportunity to target and integrate regulatory signals Mol. Cell 52 2013 517 528 24184211 PMC3845087
- Huang P. He Z. Ji S. Sun H. Xiang D. Liu C. Hu Y. Wang X. Hui L. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors Nature 475 2011 386 389 21562492
- Hwang P.I. Wu H.B. Wang C.D. Lin B.L. Chen C.T. Yuan S. Wu G. Li K.C. Tissue-specific gene expression templates for accurate molecular characterization of the normal physiological states of multiple human tissues with implication in development and cancer studies BMC Genomics 12 2011 439 21880155 PMC3178546
- Iwafuchi-Doi M. Zaret K.S. Pioneer transcription factors in cell reprogramming Genes Dev. 28 2014 2679 2692 25512556 PMC4265672
- Kamao H. Mandai M. Okamoto S. Sakai N. Suga A. Sugita S. Kiryu J. Takahashi M. Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application Stem Cell Reports 2 2014 205 218 24527394 PMC3923225
- Lang A.H. Li H. Collins J.J. Mehta P. Epigenetic landscapes explain partially reprogrammed cells and identify key reprogramming genes PLoS Comput. Biol. 10 2014 e1003734 25122086 PMC4133049
- Lujan E. Chanda S. Ahlenius H. Südhof T.C. Wernig M. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells Proc. Natl. Acad. Sci. USA 109 2012 2527 2532 22308465 PMC3289376
- Morris S.A. Daley G.Q. A blueprint for engineering cell fate: current technologies to reprogram cell identity Cell Res. 23 2013 33 48 23277278 PMC3541663
- Morris S.A. Cahan P. Li H. Zhao A.M. San Roman A.K. Shivdasani R.A. Collins J.J. Daley G.Q. Dissecting engineered cell types and enhancing cell fate conversion via CellNet Cell 158 2014 889 902 25126792 PMC4291075
- Nichols J. Zevnik B. Anastassiadis K. Niwa H. Klewe-Nebenius D. Chambers I. Schöler H. Smith A. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4 Cell 95 1998 379 391 9814708
- Parker S.C. Stitzel M.L. Taylor D.L. Orozco J.M. Erdos M.R. Akiyama J.A. van Bueren K.L. Chines P.S. Narisu N. Black B.L. NISC Comparative Sequencing Program National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program Authors NISC Comparative Sequencing Program Authors Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants Proc. Natl. Acad. Sci. USA 110 2013 17921 17926 24127591 PMC3816444
- Rivera C.M. Ren B. Mapping human epigenomes Cell 155 2013 39 55 24074860 PMC3838898
- Roost M.S. van Iperen L. Ariyurek Y. Buermans H.P. Arindrarto W. Devalla H.D. Passier R. Mummery C.L. Carlotti F. de Koning E.J. KeyGenes, a tool to probe tissue differentiation using a human fetal transcriptional atlas Stem Cell Reports 4 2015 1112 1124 26028532 PMC4472038
- Ryeom S.W. Sparrow J.R. Silverstein R.L. CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium J. Cell Sci. 109 1996 387 395 8838662
- Saint-Geniez M. Kurihara T. Sekiyama E. Maldonado A.E. D’Amore P.A. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris Proc. Natl. Acad. Sci. USA 106 2009 18751 18756 19841260 PMC2774033
- Salero E. Blenkinsop T.A. Corneo B. Harris A. Rabin D. Stern J.H. Temple S. Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives Cell Stem Cell 10 2012 88 95 22226358
- Sancho-Martinez I. Baek S.H. Izpisua Belmonte J.C. Lineage conversion methodologies meet the reprogramming toolbox Nat. Cell Biol. 14 2012 892 899 22945254
- Sheng C. Zheng Q. Wu J. Xu Z. Wang L. Li W. Zhang H. Zhao X.Y. Liu L. Wang Z. Direct reprogramming of Sertoli cells into multipotent neural stem cells by defined factors Cell Res. 22 2012 208 218 22064700 PMC3351918
- Soufi A. Donahue G. Zaret K.S. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome Cell 151 2012 994 1004 23159369 PMC3508134
- Sparrow J.R. Hicks D. Hamel C.P. The retinal pigment epithelium in health and disease Curr. Mol. Med. 10 2010 802 823 21091424 PMC4120883
- Stergachis A.B. Neph S. Reynolds A. Humbert R. Miller B. Paige S.L. Vernot B. Cheng J.B. Thurman R.E. Sandstrom R. Developmental fate and cellular maturity encoded in human regulatory DNA landscapes Cell 154 2013 888 903 23953118 PMC3962256
- Stevenson B.R. Siliciano J.D. Mooseker M.S. Goodenough D.A. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia J. Cell Biol. 103 1986 755 766 3528172 PMC2114282
- Strauss O. The retinal pigment epithelium in visual function Physiol. Rev. 85 2005 845 881 15987797
- Strunnikova N.V. Maminishkis A. Barb J.J. Wang F. Zhi C. Sergeev Y. Chen W. Edwards A.O. Stambolian D. Abecasis G. Transcriptome analysis and molecular signature of human retinal pigment epithelium Hum. Mol. Genet. 19 2010 2468 2486 20360305 PMC2876890
- Tapscott S.J. Davis R.L. Thayer M.J. Cheng P.F. Weintraub H. Lassar A.B. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts Science 242 1988 405 411 3175662
- Vierbuchen T. Wernig M. Molecular roadblocks for cellular reprogramming Mol. Cell 47 2012 827 838 23020854 PMC3809030
- Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes Cell 153 2013 307 319 23582322 PMC3653129
- Xie W. Ren B. Developmental biology. Enhancing pluripotency and lineage specification Science 341 2013 245 247 23869010
- Xu J. Du Y. Deng H. Direct lineage reprogramming: strategies, mechanisms, and applications Cell Stem Cell 16 2015 119 134 25658369
- Yamanaka S. Induced pluripotent stem cells: past, present, and future Cell Stem Cell 10 2012 678 684 22704507
- Zhang K. Liu G.H. Yi F. Montserrat N. Hishida T. Esteban C.R. Izpisua Belmonte J.C. Direct conversion of human fibroblasts into retinal pigment epithelium-like cells by defined factors Protein Cell 5 2014 48 58 24474194 PMC3938849
- Zhou J.X. Brusch L. Huang S. Predicting pancreas cell fate decisions and reprogramming with a hierarchical multi-attractor model PLoS ONE 6 2011 e14752 21423725 PMC3056652
- Ziller M.J. Edri R. Yaffe Y. Donaghey J. Pop R. Mallard W. Issner R. Gifford C.A. Goren A. Xing J. Dissecting neural differentiation regulatory networks through epigenetic footprinting Nature 518 2015 355 359 25533951 PMC4336237
Cited by
Sorted by citations
Lago, S., Nadai, M., Cernilogar, F. M., Kazerani, M., Domíniguez Moreno, H., Schotta, G., & Richter, S. N. (2021) · Nature Communications · doi:10.1038/s41467-021-24198-2 · Cited by 269 · see citing works
An extended transcription factor regulatory network controls hepatocyte identity
Dubois‐Chevalier, J., Gheeraert, C., Berthier, A., Boulet, C., Dubois, V., Guille, L., Fourcot, M., Marot, G., Gauthier, K., Dubuquoy, L., et al. (2023) · EMBO Reports · doi:10.15252/embr.202357020 · Cited by 6 · see citing works
“Hep-ID TFs were defined as hepatocyte-identity TFs retrieved in at least two out of three independent studies (D’Alessio Ana et al , 2015; Zhou et al , 2017; Dubois et al , 2020a).”
Influential
- Authors
- D’Alessio, A. C., Fan, Z. P., Wert, K. J., Baranov, P., Cohen, M. A., Saini, J. S., Cohick, E., Charniga, C., Dadon, D., Hannett, N. M., Young, M. J., Temple, S., Jaenisch, R., Lee, T. I., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Eye and Ear Infirmary (US)
- University at Albany, State University of New York (US)
- Neural Stem Cell Institute (US)
- Corresponding author
- Lee, Tong Ihn
- Young, Richard A.
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 5
- Issue
- 5
- Pages
- 763-775
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC4649293
- OpenAlex
- W1810920534
- Cited by
- 172
- References
- 7
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 19 · 2023: 14 · 2022: 22 · 2021: 22 · 2020: 18 · 2019: 14 · 2018: 15 · 2017: 18 · 2016: 15
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (HG002668, R01HG002668)
- National Cancer Institute (CA146445, R01CA146445)
- National Institute of Neurological Disorders and Stroke (R01NS088538)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- transcription factors, cell identity, transcriptional atlas, cellular reprogramming, transcriptional regulation, human cell types
- MeSH terms
- Cell Line, Computer Simulation, Epithelial Cells, Fibroblasts, Humans, Transcription Factors, Retinal Pigment Epithelium, 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