TY - JOUR
T1 - The role of chromatin accessibility in cis-regulatory evolution
AU - Peng, Pei Chen
AU - Khoueiry, Pierre
AU - Girardot, Charles
AU - Reddington, James P.
AU - Garfield, David A.
AU - Furlong, Eileen E.M.
AU - Sinha, Saurabh
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/5/22
Y1 - 2019/5/22
N2 - Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes iswellrecorded, itsrole in evolutionarydivergence of TFbinding,which inturn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases,forexample,forthemasterregulatorTwistandforearlierdevelopmentalstages,moreaccuratelypredictbinding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion ofthe codivergence of TF pairs.We notedthat accessibility and motif changes offer complementary views ofthe evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity.
AB - Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes iswellrecorded, itsrole in evolutionarydivergence of TFbinding,which inturn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases,forexample,forthemasterregulatorTwistandforearlierdevelopmentalstages,moreaccuratelypredictbinding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion ofthe codivergence of TF pairs.We notedthat accessibility and motif changes offer complementary views ofthe evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity.
KW - Chromatin accessibility
KW - Cis-regulatory evolution
KW - Enhancer activity
KW - Interspecies
KW - Sequence motif
KW - Transcription factor binding
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U2 - 10.1093/gbe/evz103
DO - 10.1093/gbe/evz103
M3 - Article
C2 - 31114856
AN - SCOPUS:85068510560
SN - 1759-6653
VL - 11
SP - 1813
EP - 1828
JO - Genome biology and evolution
JF - Genome biology and evolution
IS - 7
M1 - evz103
ER -