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DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin.

Publication ,  Journal Article
Coons, LA; Hewitt, SC; Burkholder, AB; McDonnell, DP; Korach, KS
Published in: Endocrinology
October 1, 2017

Gene regulatory programs are encoded in the sequence of the DNA. Since the completion of the Human Genome Project, millions of gene regulatory elements have been identified in the human genome. Understanding how each of those sites functionally contributes to gene regulation, however, remains a challenge for nearly every field of biology. Transcription factors influence cell function by interpreting information contained within cis-regulatory elements in chromatin. Whereas chromatin immunoprecipitation-sequencing has been used to identify and map transcription factor-DNA interactions, it has been difficult to assign functionality to the binding sites identified. Thus, in this study, we probed the transcriptional activity, DNA-binding competence, and functional activity of select nuclear receptor mutants in cellular and animal model systems and used this information to define the sequence constraints of functional steroid nuclear receptor cis-regulatory elements. Analysis of the architecture within sNR chromatin interacting sites revealed that only a small fraction of all sNR chromatin-interacting events is associated with transcriptional output and that this functionality is restricted to elements that vary from the consensus palindromic elements by one or two nucleotides. These findings define the transcriptional grammar necessary to predict functionality from regulatory sequences, with a multitude of future implications.

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Published In

Endocrinology

DOI

EISSN

1945-7170

Publication Date

October 1, 2017

Volume

158

Issue

10

Start / End Page

3212 / 3234

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factors
  • Regulatory Sequences, Nucleic Acid
  • Regulatory Elements, Transcriptional
  • Receptors, Steroid
  • Receptors, Cytoplasmic and Nuclear
  • Receptor Cross-Talk
  • Mutation
  • Mice
  • Inverted Repeat Sequences
 

Citation

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Coons, L. A., Hewitt, S. C., Burkholder, A. B., McDonnell, D. P., & Korach, K. S. (2017). DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin. Endocrinology, 158(10), 3212–3234. https://doi.org/10.1210/en.2017-00468
Coons, Laurel A., Sylvia C. Hewitt, Adam B. Burkholder, Donald P. McDonnell, and Kenneth S. Korach. “DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin.Endocrinology 158, no. 10 (October 1, 2017): 3212–34. https://doi.org/10.1210/en.2017-00468.
Coons LA, Hewitt SC, Burkholder AB, McDonnell DP, Korach KS. DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin. Endocrinology. 2017 Oct 1;158(10):3212–34.
Coons, Laurel A., et al. “DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin.Endocrinology, vol. 158, no. 10, Oct. 2017, pp. 3212–34. Pubmed, doi:10.1210/en.2017-00468.
Coons LA, Hewitt SC, Burkholder AB, McDonnell DP, Korach KS. DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin. Endocrinology. 2017 Oct 1;158(10):3212–3234.
Journal cover image

Published In

Endocrinology

DOI

EISSN

1945-7170

Publication Date

October 1, 2017

Volume

158

Issue

10

Start / End Page

3212 / 3234

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factors
  • Regulatory Sequences, Nucleic Acid
  • Regulatory Elements, Transcriptional
  • Receptors, Steroid
  • Receptors, Cytoplasmic and Nuclear
  • Receptor Cross-Talk
  • Mutation
  • Mice
  • Inverted Repeat Sequences