TY - JOUR
T1 - Regulated noise in the epigenetic landscape of development and disease
AU - Pujadas, Elisabet
AU - Feinberg, Andrew P.
N1 - Funding Information:
We thank Sean Taverna, Andre Levchenko, Winston Timp, Roger Reeves, Rolf Ohlsson, Tomas Ekstrom, Claes Wahlestedt, Brian Herb, Yun Liu, Michael Multhaup, Amy Unterman, Namyoung Jung, Onur Kilic, and Karen Reddy for reading and helpful comments during preparation of the manuscript. This work was supported by NIH Director's Pioneer Award DP1OD008324 to A.F. and NIGMS Medical Scientist Training Program Award T32-GM007309 to E.P.
PY - 2012/3/16
Y1 - 2012/3/16
N2 - In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After grounding our argument in a discussion of stochastic noise and nongenetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, thus contributing to tumor cell heterogeneity.
AB - In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After grounding our argument in a discussion of stochastic noise and nongenetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, thus contributing to tumor cell heterogeneity.
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U2 - 10.1016/j.cell.2012.02.045
DO - 10.1016/j.cell.2012.02.045
M3 - Review article
C2 - 22424224
AN - SCOPUS:84858414016
SN - 0092-8674
VL - 148
SP - 1123
EP - 1131
JO - Cell
JF - Cell
IS - 6
ER -