DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin
Year: 2017
Type: article
Abstract: 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 cisregulatory 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.(Endocrinology 158: 3212-3234, 2017) S teroid nuclear receptors (sNRs) are ligand-activated DNA-binding transcription factors (TFs) that induce or repress gene transcription following their interaction with specific DNA-binding sequences within enhancers associated with target genes (1).Specifically, sNRs mediate cellular response to their cognate hormones by interacting with DNA sequence-specific cis-regulatory elements: the estrogen response element (ERE) used by the estrogen receptors (ERs) and the hormone response element (HRE) used by the ketosteroid receptors (KRs): androgen receptor (AR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and progesterone receptor (PR) (2, 3).These DNA elements not only serve to address sNRs to target genes but also contain information that influences the transcriptional activity of bound sNRcoregulator complexes.The functionality of these response elements is defined by the context in which they operate within chromatinized DNA.However, the structural and primary sequence features that distinguish functional binding elements from those that permit sNR
Source: Endocrinology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Award: G9000228742
OpenAlex ID: W2738469793