TY - JOUR
T1 - Transcription Factor Binding in Embryonic Stem Cells Is Constrained by DNA Sequence Repeat Symmetry
AU - Goldshtein, Matan
AU - Mellul, Meir
AU - Deutch, Gai
AU - Imashimizu, Masahiko
AU - Takeuchi, Koh
AU - Meshorer, Eran
AU - Ram, Oren
AU - Lukatsky, David B.
N1 - Funding Information:
This work was supported by the Israel Science Foundation under the grant numbers 1140/17 and 2143/19 (to E.M. and O.R.). We also would like to acknowledge the funding of the European Research Council Starting Grant number 715260 .
Funding Information:
We acknowledge the generous support and professional help of Prof. Smadar Cohen and the Regenerative Medicine and Stem Cell Research Center at Ben-Gurion University of the Negev. We thank Dr. Vladimir Teif for critical reading of the manuscript. This work was supported by the Israel Science Foundation under the grant numbers 1140/17 and 2143/19 (to E.M. and O.R.). We also would like to acknowledge the funding of the European Research Council Starting Grant number 715260.
Publisher Copyright:
© 2020 Biophysical Society
PY - 2020/4/21
Y1 - 2020/4/21
N2 - Transcription factor (TF) recognition is dictated by the underlying DNA motif sequence specific for each TF. Here, we reveal that DNA sequence repeat symmetry plays a central role in defining TF-DNA-binding preferences. In particular, we find that different TFs bind similar symmetry patterns in the context of different developmental layers. Most TFs possess dominant preferences for similar DNA repeat symmetry types. However, in some cases, preferences of specific TFs are changed during differentiation, suggesting the importance of information encoded outside of known motif regions. Histone modifications also exhibit strong preferences for similar DNA repeat symmetry patterns unique to each type of modification. Next, using an in vivo reporter assay, we show that gene expression in embryonic stem cells can be positively modulated by the presence of genomic and computationally designed DNA oligonucleotides containing identified nonconsensus-repetitive sequence elements. This supports the hypothesis that certain nonconsensus-repetitive patterns possess a functional ability to regulate gene expression. We also performed a solution NMR experiment to probe the stability of double-stranded DNA via imino proton resonances for several double-stranded DNA sequences characterized by different repetitive patterns. We suggest that such local stability might play a key role in determining TF-DNA binding preferences. Overall, our findings show that despite the enormous sequence complexity of the TF-DNA binding landscape in differentiating embryonic stem cells, this landscape can be quantitatively characterized in simple terms using the notion of DNA sequence repeat symmetry.
AB - Transcription factor (TF) recognition is dictated by the underlying DNA motif sequence specific for each TF. Here, we reveal that DNA sequence repeat symmetry plays a central role in defining TF-DNA-binding preferences. In particular, we find that different TFs bind similar symmetry patterns in the context of different developmental layers. Most TFs possess dominant preferences for similar DNA repeat symmetry types. However, in some cases, preferences of specific TFs are changed during differentiation, suggesting the importance of information encoded outside of known motif regions. Histone modifications also exhibit strong preferences for similar DNA repeat symmetry patterns unique to each type of modification. Next, using an in vivo reporter assay, we show that gene expression in embryonic stem cells can be positively modulated by the presence of genomic and computationally designed DNA oligonucleotides containing identified nonconsensus-repetitive sequence elements. This supports the hypothesis that certain nonconsensus-repetitive patterns possess a functional ability to regulate gene expression. We also performed a solution NMR experiment to probe the stability of double-stranded DNA via imino proton resonances for several double-stranded DNA sequences characterized by different repetitive patterns. We suggest that such local stability might play a key role in determining TF-DNA binding preferences. Overall, our findings show that despite the enormous sequence complexity of the TF-DNA binding landscape in differentiating embryonic stem cells, this landscape can be quantitatively characterized in simple terms using the notion of DNA sequence repeat symmetry.
UR - http://www.scopus.com/inward/record.url?scp=85080025026&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2020.02.009
DO - 10.1016/j.bpj.2020.02.009
M3 - Article
C2 - 32101712
AN - SCOPUS:85080025026
SN - 0006-3495
VL - 118
SP - 2015
EP - 2026
JO - Biophysical Journal
JF - Biophysical Journal
IS - 8
ER -