Molecular Roadblocks for Cellular Reprogramming
Thomas Vierbuchen1,2and Marius Wernig1,*
1Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, and Cancer Biology Program, Stanford University
School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA
2Present Address: Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
During development, diverse cellular identities are established and maintained in the embryo. Although
remarkably robust in vivo, cellular identities can be manipulated using experimental techniques. Lineage
reprogramming is an emerging field at the intersection of developmental and stem cell biology in which
a somatic cell is stably reprogrammed into a distinct cell type by forced expression of lineage-determining
factors. Lineage reprogramming enables the direct conversion of readily available cells from patients
(such as skin fibroblasts) into disease-relevant cell types (such as neurons and cardiomyocytes) or into
induced pluripotent stem cells. Although remarkable progress has been made in developing novel reprog-
ramming methods, the efficiency and fidelity of reprogramming need to be improved in order increase
the experimental and translational utility of reprogrammed cells. Studying the mechanisms that prevent
successful reprogramming should allow for improvements in reprogramming methods, which could have
significant implications for regenerative medicine and the study of human disease. Furthermore, lineage
reprogramming has the potential to become a powerful system for dissecting the mechanisms that underlie
cell fate establishment and terminal differentiation processes. In this review, we will discuss how transcrip-
tion factors interface with the genome and induce changes in cellular identity in the context of development
During development, cell fate is established and maintained by
complex regulatory networks of transcription factors that
promote expression of cell type-specific gene products and
repress regulators of other lineages. Once established, cellular
identity is remarkably stable despite numerous intrinsic and
extrinsic perturbations. This stability is likely the result of a
combination of multiple molecular features, including cis-
acting epigenetic modifications, such as DNA methylation,
posttranslational modifications of histone tails, nucleosome
positioning, incorporation of histone variants into nucleosomes,
and trans-acting regulatory factors such as sequence-specific
DNA-binding transcription factors, transcriptional coactivators,
noncoding RNAs, and chromatin remodeling complexes (Graf
and Enver, 2009; Ho and Crabtree, 2010; Yamanaka and Blau,
2010). Although generally stable in vivo, under certain experi-
mental conditions, cell fate can be dominantly reprogrammed
by forcing expression of transcription factors involved in the
establishment and maintenance of a distinct cellular lineage
(Figure 1). Identifying the relevant stimuli that can reprogram
one cell into another cell type of interest and understanding
how this process occurs are two key goals for the reprogram-
In this review, we will summarize the critical discoveries to
date, but only briefly discuss applications of cellular reprogram-
ming technologies for understanding human disease and
regenerative medicine (for more detailed reviews on these topics
see Graf, 2011; Gurdon, 2006; Holmberg and Perlmann, 2012;
Saha and Jaenisch, 2009; Vierbuchen and Wernig, 2011) and
instead focus on selected discoveries that have helped to iden-
ming. Furthermore, we propose that the nonphysiological direct
lineage reprogramming approaches will be useful for studying
physiological mechanisms of transcriptional reprogramming,
such as the establishment of cellular identity, as well as the
transcriptional regulatory networks that drive terminal differenti-
ation and functional maturation (Bussmann et al., 2009; Graf and
Enver, 2009; Vierbuchen and Wernig, 2011).
Brief Overview of Critical Discoveries in Epigenetic
Seminal work by Briggs, King, and Gurdon in the 1950s demon-
strated thatthe stability ofthe differentiated state isnottheresult
of irreversible genomic changes that occur during differentiation
(Briggs and King, 1952; Gurdon et al., 1958). This was demon-
strated by Somatic Cell Nuclear Transfer (SCNT), a technique in
which intact Xenopus nuclei from embryonic or adult cells are
transferred into an enucleated oocyte. Gurdon used this system
to demonstrate that nuclei from endoderm cells taken from tail-
bud stage frog embryos could successfully control the develop-
ment of new tadpoles. Later work showed that even nuclei from
terminally differentiated adult cells (e.g., blood cells, skeletal
muscle, kidney, and others) could generate Xenopus larvae
following nuclear transfer, albeit at reduced efficiency compared
to nuclei from embryonic cells (Gurdon, 2006; Pasque et al.,
2011). These results indicated that the oocyte contained power-
ful trans-acting reprogramming factors that could effectively
erase somatic epigenetic marks and return nuclei from differen-
tiated cells to a pluripotent state. However, it was not clear
whether these results were a testament to the unique molecular
Molecular Cell 47, September 28, 2012 ª2012 Elsevier Inc.
properties of oocytes or to the inherent plasticity of epigenetic
modifications acquired during development.
somatic cells could also exhibit cell fate plasticity (Taylor and
Jones, 1979). They found that treatment with 5-azacytidine, an
inhibitor of DNA methylation, caused fibroblasts to spontane-
ously differentiate into muscle and fat cells. This suggested
that DNA methylation is important for preventing expression of
genes that regulate differentiation into alternative lineages. In
the early 1980s,Blau and colleagues demonstrated thatmultinu-
cleated myotubes could dominantly reprogram nuclei from other
cell types to express muscle-specific gene products in hetero-
karyons (artificially fused cells that maintain distinct nuclei),
suggesting that reprogramming activity was not unique to the
oocyte and that the terminally differentiated state was actively
Figure 1. Experimental Systems for
Studying Nuclear Reprogramming
(A) Somatic cell nuclear transfer (SCNT). Nucleus
from a donor cell is inserted into an enucleated
oocyte. In mammals, the resulting cell can then be
cultured in vitro to derive nuclear transfer ESCs
(NT-ESCs), which can then be used to generate
cloned mice via standard blastocyst injection.
Alternatively, blastocysts can be derived from
oocytes in vitro (at low efficiency) and implanted
into pseudopregnant mice to develop. Measure-
ments of the efficiency of NT-ESC derivation,
blastocyst derivation from somatic nuclei, or the
generation of live pups can serve as a measure of
the efficiency of nuclear reprogramming.
(B) Cell fusion. Two distinct cell types are fused
together to generate chimeric cells with multiple
nuclei. In order to facilitate identification of tran-
scripts or proteins from each fusion partner, cells
from different species (e.g., human and mouse)
are often used. Fused cells can be purified using
fluorescent-activated cell sorting or by double
antibiotic selection. In heterokaryons, fused cells
maintain distinct nuclei and do not undergo cell
division (e.g., Bhutani et al., 2010). Cells can
also be selected for stable, dividing clones in
which nuclear fusion has occurred. These are
referred to as synkaryons or cell hybrids (e.g.,
Cowan et al., 2005).
(C) Transcription factor-mediated reprogramming.
Reprogramming transcription factors are intro-
or RNA transfection. Numerous cell fates can be
induced in addition to those shown in the figure
(see Figure 2 for a complete list). Strong artificial
promoters are generally used to ensure robust
expression. Inducible promoters (e.g., tetracy-
cline-inducible) can be used to shut off re-
programming factor expression to determine
whether cell fate reprogramming is stable in the
absence of exogenous of transcription factor
maintained by specific groups of trans-
acting factors (Blau et al., 1983). In 1987
Weintraub and colleagues showed that
the basic helix-loop-helix (bHLH) tran-
scription factor MyoD is sufficient to
convert fibroblasts into contracting myo-
cytes (Davis et al., 1987). However, when
retinal pigment epithelium, melanocytes, hepatocytes), activa-
tion of muscle markers was sometimes observed, but complete
reprogramming failed (Weintraub et al., 1989). This suggested
that a single transcription factor can be sufficient to initiate and
control the differentiation of a specific cell type, which provided
a possible mechanism for the control of terminal differentiation
processes during development (Weintraub, 1993). Gehring and
colleagues also provided dramatic proof of this principle by
showing that ectopic expression of the transcription factor
eyeless (Pax6 in mammals), a master regulator of eye develop-
ment, could generate functional eyes at various sites on the
body (Halder et al., 1995).
In 1996, Wilmut and colleagues successfully generated live
offspring from the nucleus of a mammalian somatic cell
Molecular Cell 47, September 28, 2012 ª2012 Elsevier Inc.
Gaetz, J., Clift, K.L., Fernandes, C.J., Mao, F.F., Lee, J.H., Zhang, L., Baker,
S.W., Looney, T.J., Foshay, K.M., Yu, W.H., et al. (2012). Evidence for a critical
role of gene occlusion in cell fate restriction. Cell Res. 22, 848–858.
Graf, T. (2011). Historical origins of transdifferentiation and reprogramming.
Cell Stem Cell 9, 504–516.
Graf, T., and Enver, T. (2009). Forcing cells to change lineages. Nature 462,
Gurdon, J.B. (2006). From nuclear transfer to nuclear reprogramming: the
reversal of cell differentiation. Annu. Rev. Cell Dev. Biol. 22, 1–22.
Gurdon, J.B., Elsdale, T.R., and Fischberg, M. (1958). Sexually mature
individuals of Xenopus laevis from the transplantation of single somatic nuclei.
Nature 182, 64–65.
Halder, G., Callaerts, P., and Gehring, W.J. (1995). Induction of ectopic eyes
by targeted expression of the eyeless gene in Drosophila. Science 267,
Han, S.S., Williams, L.A., and Eggan, K.C. (2011). Constructing and decon-
structing stem cell models of neurological disease. Neuron 70, 626–644.
Hanna, J., Markoulaki, S., Schorderet, P., Carey, B.W., Beard, C., Wernig, M.,
Creyghton, M.P., Steine, E.J., Cassady, J.P., Foreman, R., et al. (2008).
Direct reprogramming of terminally differentiated mature B lymphocytes to
pluripotency. Cell 133, 250–264.
Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C.J., Creyghton, M.P.,
van Oudenaarden, A., and Jaenisch, R. (2009). Direct cell reprogramming is
a stochastic process amenable to acceleration. Nature 462, 595–601.
Hanna, J.H., Saha, K., and Jaenisch, R. (2010). Pluripotency and cellular
reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508–525.
Heinrich, C., Blum, R., Gasco ´n, S., Masserdotti, G., Tripathi, P., Sa ´nchez, R.,
Tiedt, S., Schroeder, T., Go ¨tz, M., and Berninger, B. (2010). Directing astroglia
fromthecerebralcortex intosubtype specificfunctional neurons.PLoS Biol. 8,
Heins, N., Malatesta, P., Cecconi, F., Nakafuku, M., Tucker, K.L., Hack, M.A.,
Chapouton, P., Barde, Y.A., and Go ¨tz, M. (2002). Glial cells generate neurons:
the role of the transcription factor Pax6. Nat. Neurosci. 5, 308–315.
Ho, L., and Crabtree,G.R. (2010). Chromatin remodelling during development.
Nature 463, 474–484.
Hochedlinger, K., and Jaenisch, R. (2002). Monoclonal mice generated by
nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038.
Hochedlinger, K., and Jaenisch, R. (2006). Nuclear reprogramming and plurip-
otency. Nature 441, 1061–1067.
Hochedlinger,K.,and Plath,K.(2009).Epigenetic reprogramming andinduced
pluripotency. Development 136, 509–523.
Holmberg, J., and Perlmann, T. (2012). Maintaining differentiated cellular iden-
tity. Nat. Rev. Genet. 13, 429–439.
Hornstein, E., and Shomron, N. (2006). Canalization of development by micro-
RNAs. Nat. Genet. Suppl. 38, S20–S24.
Huang,P.,He, Z.,Ji, S.,Sun,H., Xiang,D., Liu,C., Hu,Y.,Wang, X.,and Hui, L.
(2011). Induction of functional hepatocyte-like cells from mouse fibroblasts
by defined factors. Nature 475, 386–389.
Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A.E.,
and Melton, D.A. (2008). Induction of pluripotent stem cells by defined
factors is greatly improved by small-molecule compounds. Nat. Biotechnol.
Ieda, M., Fu, J.D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau,
B.G., and Srivastava, D. (2010). Direct reprogramming of fibroblasts into
functional cardiomyocytes by defined factors. Cell 142, 375–386.
John, S., Sabo, P.J., Thurman, R.E., Sung, M.H., Biddie, S.C., Johnson, T.A.,
Hager, G.L., and Stamatoyannopoulos, J.A. (2011). Chromatin accessibility
pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43,
Kajimura, S., Seale, P., Kubota, K., Lunsford, E., Frangioni, J.V., Gygi, S.P.,
and Spiegelman, B.M. (2009). Initiation of myoblast to brown fat switch by
a PRDM16-C/EBP-beta transcriptional complex. Nature 460, 1154–1158.
Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R., Cahan, P., Kim, J., Aryee, M.J., Ji,
H., Ehrlich, L.I., et al. (2010). Epigenetic memory in induced pluripotent stem
cells. Nature 467, 285–290.
Kim, K., Zhao, R., Doi, A., Ng, K., Unternaehrer, J., Cahan, P., Huo, H., Loh,
Y.H., Aryee, M.J., Lensch, M.W., et al. (2011). Donor cell type can influence
the epigenome and differentiation potential of human induced pluripotent
stem cells. Nat. Biotechnol. 29, 1117–1119.
Koche, R.P., Smith, Z.D., Adli, M., Gu, H., Ku, M., Gnirke, A., Bernstein, B.E.,
and Meissner, A. (2011). Reprogramming factor expression initiates wide-
spread targeted chromatin remodeling. Cell Stem Cell 8, 96–105.
Lahn, B.T. (2011). The ‘‘occlusis’’ model of cell fate restriction. Bioessays 33,
Li, G., Levitus, M., Bustamante, C., and Widom, J. (2005). Rapid spontaneous
accessibility of nucleosomal DNA. Nat. Struct. Mol. Biol. 12, 46–53.
Lujan, E., Chanda, S., Ahlenius, H., Su ¨dhof, T.C., and Wernig,M. (2012). Direct
conversion of mouse fibroblasts to self-renewing, tripotent neural precursor
cells. Proc. Natl. Acad. Sci. USA 109, 2527–2532.
Machlin, E.S., Sarnow, P., and Sagan, S.M. (2011). Masking the 5’ terminal
nucleotides of the hepatitis C virus genome by an unconventional micro-
RNA-target RNA complex. Proc. Natl. Acad. Sci. USA 108, 3193–3198.
Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld,
M., Yachechko, R., Tchieu, J., Jaenisch, R., et al. (2007). Directly reprog-
rammed fibroblasts show global epigenetic remodeling and widespread
tissue contribution. Cell Stem Cell 1, 55–70.
Marro, S., Pang, Z.P., Yang, N., Tsai, M.C., Qu, K., Chang, H.Y., Su ¨dhof, T.C.,
and Wernig, M. (2011). Direct lineage conversion of terminally differentiated
hepatocytes to functional neurons. Cell Stem Cell 9, 374–382.
Meissner, A., Wernig, M., and Jaenisch, R. (2007). Direct reprogramming of
genetically unmodified fibroblasts into pluripotent stem cells. Nat. Biotechnol.
Miller, S.C., Pavlath, G.K., Blakely, B.T., and Blau, H.M. (1988). Muscle cell
components dictate hepatocyte gene expression and the distribution of the
Golgi apparatus in heterokaryons. Genes Dev. 2, 330–340.
Ming, G.L., Bru ¨stle, O., Muotri, A., Studer, L., Wernig, M., and Christian, K.M.
(2011). Cellular reprogramming: recent advances in modeling neurological
diseases. J. Neurosci. 31, 16070–16075.
Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K.,
Maruyama, M., Maeda, M., and Yamanaka, S. (2003). The homeoprotein
Nanog is required for maintenance of pluripotency in mouse epiblast and ES
cells. Cell 113, 631–642.
Miyoshi, N., Ishii, H., Nagano, H., Haraguchi, N., Dewi, D.L., Kano, Y.,
Nishikawa, S., Tanemura, M., Mimori, K., Tanaka, F., et al. (2011). Reprogram-
ming of mouse and human cells to pluripotency using mature microRNAs. Cell
Stem Cell 8, 633–638.
Ng, R.K., and Gurdon, J.B. (2005). Epigenetic memory of active gene
transcription is inherited through somatic cell nuclear transfer. Proc. Natl.
Acad. Sci. USA 102, 1957–1962.
Ng, R.K., and Gurdon, J.B. (2008). Epigenetic memory of an active gene state
depends on histone H3.3 incorporation into chromatin in the absence of
transcription. Nat. Cell Biol. 10, 102–109.
Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-
competent induced pluripotent stem cells. Nature 448, 313–317.
Palermo, A., Doyonnas, R., Bhutani, N., Pomerantz, J., Alkan, O., and Blau,
H.M. (2009). Nuclear reprogramming in heterokaryons is rapid, extensive,
and bidirectional. FASEB J. 23, 1431–1440.
Palii, C.G., Perez-Iratxeta, C., Yao, Z., Cao, Y., Dai, F., Davison, J., Atkins, H.,
Allan, D., Dilworth, F.J., Gentleman, R., et al. (2011). Differential genomic
targeting of the transcription factor TAL1 in alternate haematopoietic lineages.
EMBO J. 30, 494–509.
Molecular Cell 47, September 28, 2012 ª2012 Elsevier Inc.
Pang, Z.P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D.R., Yang,
T.Q., Citri, A., Sebastiano, V., Marro, S., Su ¨dhof, T.C., and Wernig, M.
(2011). Induction of human neuronal cells by defined transcription factors.
Nature 476, 220–223.
Pasque, V., Jullien, J., Miyamoto, K., Halley-Stott, R.P., and Gurdon, J.B.
(2011). Epigenetic factors influencing resistance to nuclear reprogramming.
Trends Genet. 27, 516–525.
Pereira, C.F., Terranova, R., Ryan, N.K., Santos, J., Morris, K.J., Cui, W.,
Merkenschlager, M., and Fisher, A.G. (2008). Heterokaryon-based reprogram-
ming of human B lymphocytes for pluripotency requires Oct4 but not Sox2.
PLoS Genet. 4, e1000170.
Pereira, C.F., Piccolo, F.M., Tsubouchi, T., Sauer, S., Ryan, N.K., Bruno, L.,
Landeira, D., Santos, J., Banito, A., Gil, J., et al. (2010). ESCs require PRC2
to direct the successful reprogramming of differentiated cells toward pluripo-
tency. Cell Stem Cell 6, 547–556.
Pfisterer, U., Kirkeby, A., Torper, O., Wood, J., Nelander, J., Dufour, A.,
Bjo ¨rklund, A., Lindvall, O., Jakobsson, J., and Parmar, M. (2011). Direct
conversion of human fibroblasts to dopaminergic neurons. Proc. Natl. Acad.
Sci. USA 108, 10343–10348.
Piccolo, F.M., Pereira, C.F., Cantone, I., Brown, K., Tsubouchi, T., Soza-Ried,
J., Merkenschlager, M., and Fisher, A.G. (2011). Using heterokaryons to
understand pluripotency and reprogramming. Philos. Trans. R. Soc. Lond. B
Biol. Sci. 366, 2260–2265.
Polo, J.M., Liu, S., Figueroa, M.E., Kulalert, W., Eminli, S., Tan, K.Y.,
Apostolou, E., Stadtfeld, M., Li, Y., Shioda, T., et al. (2010). Cell type of origin
influences the molecular and functional properties of mouse induced pluripo-
tent stem cells. Nat. Biotechnol. 28, 848–855.
Probst, A.V., Dunleavy, E., and Almouzni, G. (2009). Epigenetic inheritance
during the cell cycle. Nat. Rev. Mol. Cell Biol. 10, 192–206.
Qiang, L., Fujita, R., Yamashita, T., Angulo, S., Rhinn, H., Rhee, D., Doege, C.,
Chau, L., Aubry, L., Vanti, W.B., et al. (2011). Directed conversion of
Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell 146,
Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S.A., Flynn, R.A., and
Wysocka, J. (2011). A unique chromatin signature uncovers early develop-
mental enhancers in humans. Nature 470, 279–283.
Saha, K., and Jaenisch, R. (2009). Technical challenges in using human
induced pluripotent stem cells to model disease. Cell Stem Cell 5, 584–595.
Scha ¨fer, B.W., Blakely, B.T., Darlington, G.J., and Blau, H.M. (1990). Effect of
cell history on response to helix-loop-helix family of myogenic regulators.
Nature 344, 454–458.
Sekiya, S., and Suzuki, A. (2011). Direct conversion of mouse fibroblasts to
hepatocyte-like cells by defined factors. Nature 475, 390–393.
Shen, C.N., Slack, J.M., and Tosh, D. (2000). Molecular basis of transdifferen-
tiation of pancreas to liver. Nat. Cell Biol. 2, 879–887.
Silva, J., and Smith, A. (2008). Capturing pluripotency. Cell 132, 532–536.
Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J.,
and Eggan, K. (2011). Conversion of mouse and human fibroblasts into
functional spinal motor neurons. Cell Stem Cell 9, 205–218.
Sridharan, R., Tchieu, J., Mason, M.J., Yachechko, R., Kuoy, E., Horvath, S.,
Zhou, Q., and Plath, K. (2009). Role of the murine reprogramming factors in
the induction of pluripotency. Cell 136, 364–377.
Stadtfeld, M., Apostolou, E., Ferrari, F., Choi, J., Walsh, R.M., Chen, T., Ooi,
S.S., Kim, S.Y., Bestor, T.H., Shioda, T., et al. (2012). Ascorbic acid prevents
loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice
from terminally differentiated B cells. Nat Genet 44, 398–405, S391–S392.
Sun, Y., Nadal-Vicens, M., Misono, S., Lin, M.Z., Zubiaga, A., Hua, X., Fan, G.,
and Greenberg, M.E. (2001). Neurogenin promotes neurogenesis and inhibits
glial differentiation by independent mechanisms. Cell 104, 365–376.
Szabo, E., Rampalli, S., Risuen ˜o, R.M., Schnerch, A., Mitchell, R., Fiebig-
Comyn, A., Levadoux-Martin, M., and Bhatia, M. (2010). Direct conversion of
human fibroblasts to multilineage blood progenitors. Nature 468, 521–526.
Taberlay, P.C., Kelly, T.K., Liu, C.C., You, J.S., De Carvalho, D.D., Miranda,
T.B.,Zhou, X.J., Liang,G.,and Jones, P.A.(2011). Polycomb-repressedgenes
have permissive enhancers that initiate reprogramming. Cell 147, 1283–1294.
Tada, M., Takahama, Y., Abe, K., Nakatsuji, N., and Tada, T. (2001). Nuclear
reprogramming of somatic cells by in vitro hybridization with ES cells. Curr.
Biol. 11, 1553–1558.
Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells
from mouse embryonic and adult fibroblast cultures by defined factors. Cell
Tapscott, S.J. (2005). Thecircuitry ofamaster switch: Myod and theregulation
of skeletal muscle gene transcription. Development 132, 2685–2695.
Taylor, S.M., and Jones, P.A. (1979). Multiple new phenotypes induced in
10T1/2 and 3T3 cells treated with 5-azacytidine. Cell 17, 771–779.
Vierbuchen, T., and Wernig, M. (2011). Direct lineage conversions: unnatural
but useful? Nat. Biotechnol. 29, 892–907.
Vierbuchen, T., Ostermeier, A., Pang, Z.P., Kokubu, Y., Su ¨dhof, T.C., and
Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by
defined factors. Nature 463, 1035–1041.
Wakayama, T., Perry, A.C., Zuccotti, M., Johnson, K.R., and Yanagimachi, R.
(1998). Full-term development of mice from enucleated oocytes injected with
cumulus cell nuclei. Nature 394, 369–374.
Weintraub, H. (1993). The MyoD family and myogenesis: redundancy,
networks, and thresholds. Cell 75, 1241–1244.
Weintraub, H., Tapscott, S.J., Davis, R.L., Thayer, M.J., Adam, M.A., Lassar,
A.B., and Miller, A.D. (1989). Activation of muscle-specific genes in pigment,
nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD.
Proc. Natl. Acad. Sci. USA 86, 5434–5438.
Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger,
K., Bernstein, B.E., and Jaenisch, R. (2007). In vitro reprogramming of
fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324.
Wilson, N.K., Foster, S.D., Wang, X., Knezevic, K., Schu ¨tte, J., Kaimakis, P.,
Chilarska, P.M., Kinston, S., Ouwehand, W.H., Dzierzak, E., et al. (2010).
genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell
in bloodstem/progenitor cells:
Xie, H., Ye, M., Feng, R., and Graf, T. (2004). Stepwise reprogramming of
B cells into macrophages. Cell 117, 663–676.
Xu, Y., Shi, Y., and Ding, S. (2008). A chemical approach to stem-cell biology
and regenerative medicine. Nature 453, 338–344.
Yamanaka, S., and Blau, H.M. (2010). Nuclear reprogramming to a pluripotent
state by three approaches. Nature 465, 704–712.
Yoo, A.S., Staahl, B.T., Chen, L., and Crabtree, G.R. (2009). MicroRNA-
mediated switching of chromatin-remodelling complexes in neural develop-
ment. Nature 460, 642–646.
C., Dolmetsch, R.E., Tsien, R.W., and Crabtree, G.R. (2011). MicroRNA-
mediated conversion of human fibroblasts to neurons. Nature 476, 228–231.
Zaret, K.S., and Carroll, J.S. (2011). Pioneer transcription factors: establishing
competence for gene expression. Genes Dev. 25, 2227–2241.
Zhou, Q., and Melton, D.A. (2008). Extreme makeover: converting one cell into
another. Cell Stem Cell 3, 382–388.
reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455,
Molecular Cell 47, September 28, 2012 ª2012 Elsevier Inc.