scholarly journals Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

2019 ◽  
Author(s):  
Avital Sarusi Portuguez ◽  
Ivana Grbesa ◽  
Moran Tal ◽  
Rachel Deitch ◽  
Dana Raz ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Binding Sites ◽  
Gene Activation ◽  
Spatial Separation ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Chromatin Binding ◽  
Physiological Processes ◽  
Regulatory Loci ◽  
Open Question

ABSTRACTThe transcription factor glucocorticoid receptor (GR) is a key mediator of stress response and a broad range of physiological processes. How can GR rapidly activate the expression of some genes while repress others, remains an open question due to the challenge to associate GR binding sites (GBSs) to their distant gene targets. Mapping the full 3D scope of GR-responsive promoters using high-resolution 4C-seq unravelled spatial separation between chromatin interaction networks of GR-activated and repressed genes. Analysing GR binding sites and other regulatory loci in their functional 3D context revealed that GR sequesters the co-activator Ep300 from active non-GBS enhancers in both activated and repressed gene compartments. While this is sufficient for rapid gene repression, gene activation is countered by productive recruitment of Ep300 to GBS. Importantly, in GR-activated compartments Klf4 binding at non-GBS regulatory elements cluster in 3D with GBS and antagonizes GR activation. In addition, we revealed ROR and Rev-erb transcription factors as novel co-regulators for GR-mediated gene expression.

scholarly journals The native cistrome and sequence motif families of the maize ear

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009689
Author(s):  
Savannah D. Savadel ◽  
Thomas Hartwig ◽  
Zachary M. Turpin ◽  
Daniel L. Vera ◽  
Pei-Yau Lung ◽  
...  
Keyword(s):  
High Resolution ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Sequence Motif ◽  
Binding Prediction ◽  
Interaction Sites ◽  
Genome Wide ◽  
Dna Regulatory Elements

Elucidating the transcriptional regulatory networks that underlie growth and development requires robust ways to define the complete set of transcription factor (TF) binding sites. Although TF-binding sites are known to be generally located within accessible chromatin regions (ACRs), pinpointing these DNA regulatory elements globally remains challenging. Current approaches primarily identify binding sites for a single TF (e.g. ChIP-seq), or globally detect ACRs but lack the resolution to consistently define TF-binding sites (e.g. DNAse-seq, ATAC-seq). To address this challenge, we developed MNase-defined cistrome-Occupancy Analysis (MOA-seq), a high-resolution (< 30 bp), high-throughput, and genome-wide strategy to globally identify putative TF-binding sites within ACRs. We used MOA-seq on developing maize ears as a proof of concept, able to define a cistrome of 145,000 MOA footprints (MFs). While a substantial majority (76%) of the known ATAC-seq ACRs intersected with the MFs, only a minority of MFs overlapped with the ATAC peaks, indicating that the majority of MFs were novel and not detected by ATAC-seq. MFs were associated with promoters and significantly enriched for TF-binding and long-range chromatin interaction sites, including for the well-characterized FASCIATED EAR4, KNOTTED1, and TEOSINTE BRANCHED1. Importantly, the MOA-seq strategy improved the spatial resolution of TF-binding prediction and allowed us to identify 215 motif families collectively distributed over more than 100,000 non-overlapping, putatively-occupied binding sites across the genome. Our study presents a simple, efficient, and high-resolution approach to identify putative TF footprints and binding motifs genome-wide, to ultimately define a native cistrome atlas.

Human IL-12(p35) gene activation involves selective remodeling of a single nucleosome within a region of the promoter containing critical Sp1-binding sites

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4894-4902 ◽  
Author(s):  
Stanislas Goriely ◽  
Dominique Demonté ◽  
Séverine Nizet ◽  
Dominique De Wit ◽  
Fabienne Willems ◽  
...  
Keyword(s):  
Cell Line ◽  
Chromatin Remodeling ◽  
Binding Sites ◽  
Gene Activation ◽  
Regulatory Elements ◽  
Micrococcal Nuclease ◽  
Interleukin 12 ◽  
P35 Gene ◽  
Free Region ◽  
Ifn Γ

AbstractTo get insight into the regulation of human interleukin-12 (IL-12) synthesis, we determined the chromatin organization of the IL-12(p35) promoter region. First, we determined positioning of nucleosomes within the IL-12(p35) promoter using the indirect end-labeling technique in the THP-1 monocytic cell line. On stimulation with bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ), hypersensitivity to digestion with DNase I, micrococcal nuclease, and specific restriction enzymes was detected in the region encompassing nucleotide (nt) –310 to –160, indicating selective inducible chromatin remodeling involving disruption of a single nucleosome (named nuc-2). Using p35 promoter deletion mutants and reporter gene assays, we demonstrated that the –396/–241 region contained critical cis-acting elements. Within this latter region, we characterized physically and functionally 2 Sp1-binding sites, which were acting as key regulatory elements for both basal and LPS/IFN-γ–inducible p35 gene expression: Sp1#1 lies within the remodeled nuc-2 region and Sp1#2 is located in the nucleosome-free region immediately upstream of nuc-2. Finally, we extended the chromatin structure analysis to dendritic cells (DCs) derived from human monocytes and observed the same nucleosomal organization and remodeling as in the THP-1 cell line. Moreover, we found that in DCs, LPS and IFN-γ synergized in the induction of nucleosomal remodeling and that chromatin remodeling at the p35 locus immediately preceded IL-12(p35) mRNA synthesis. Taken together, our results demonstrate that IL-12(p35) gene activation in the course of DC maturation involves selective and rapid remodeling of a single positioned nucleosome within a region of the promoter containing critical Sp1-binding sites.

Different regions of the estrogen receptor are required for synergistic action with the glucocorticoid and progesterone receptors

1989 ◽  
Vol 9 (12) ◽  
pp. 5324-5330
Author(s):  
A C Cato ◽  
H Ponta
Keyword(s):  
Estrogen Receptor ◽  
Glucocorticoid Receptor ◽  
Binding Sites ◽  
Glucocorticoid Receptors ◽  
Steroid Receptors ◽  
Gene Activation ◽  
Synergistic Action ◽  
Receptor Expression ◽  
Expression Vectors ◽  
Mutant Receptor

Estrogen and progesterone or estrogen and glucocorticoid receptors functionally cooperate in gene activation if their cognate binding sites are close to one another. These interactions have been described as synergism of action of the steroid receptors. The mechanism by which synergism is achieved is not clear, although protein-protein interaction of the receptors is one of the favorite models. In transfection experiments with receptor expression vectors and a reporter gene containing estrogen and progesterone-glucocorticoid receptor binding sites, we have examined the effects that different portions of the various receptors have on synergism. N-terminal domains of the chicken progesterone and human glucocorticoid receptors, when deleted, abolished the synergistic action of these receptors with the estrogen receptor. Deletion of the carboxy-terminal amino acids 341 to 595 of the estrogen receptor produced a mutant receptor that could not trans-activate on its own. This mutant receptor did not affect the action of the glucocorticoid receptor but functioned synergistically with the progesterone receptor. We therefore conclude that the synergistic action of the receptors for estrogen and progesterone is mechanistically different from the synergistic action of the receptors for estrogen and glucocorticoid.

scholarly journals Different regions of the estrogen receptor are required for synergistic action with the glucocorticoid and progesterone receptors.

1989 ◽  
Vol 9 (12) ◽  
pp. 5324-5330 ◽  
Author(s):  
A C Cato ◽  
H Ponta
Keyword(s):  
Estrogen Receptor ◽  
Glucocorticoid Receptor ◽  
Binding Sites ◽  
Glucocorticoid Receptors ◽  
Steroid Receptors ◽  
Gene Activation ◽  
Synergistic Action ◽  
Receptor Expression ◽  
Expression Vectors ◽  
Mutant Receptor

Estrogen and progesterone or estrogen and glucocorticoid receptors functionally cooperate in gene activation if their cognate binding sites are close to one another. These interactions have been described as synergism of action of the steroid receptors. The mechanism by which synergism is achieved is not clear, although protein-protein interaction of the receptors is one of the favorite models. In transfection experiments with receptor expression vectors and a reporter gene containing estrogen and progesterone-glucocorticoid receptor binding sites, we have examined the effects that different portions of the various receptors have on synergism. N-terminal domains of the chicken progesterone and human glucocorticoid receptors, when deleted, abolished the synergistic action of these receptors with the estrogen receptor. Deletion of the carboxy-terminal amino acids 341 to 595 of the estrogen receptor produced a mutant receptor that could not trans-activate on its own. This mutant receptor did not affect the action of the glucocorticoid receptor but functioned synergistically with the progesterone receptor. We therefore conclude that the synergistic action of the receptors for estrogen and progesterone is mechanistically different from the synergistic action of the receptors for estrogen and glucocorticoid.

scholarly journals Dissecting super-enhancer hierarchy based on chromatin interactions

2017 ◽  
Author(s):  
Jialiang Huang ◽  
Kailong Li ◽  
Wenqing Cai ◽  
Xin Liu ◽  
Yuannyu Zhang ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Binding Sites ◽  
Structural Organization ◽  
Gene Activation ◽  
Regulatory Elements ◽  
Ctcf Binding ◽  
Intrinsic Properties ◽  
Genetic Ablation ◽  
Chromatin Interactions ◽  
Super Enhancer

AbstractRecent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants. Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape. As such, hub enhancers are the major constituents responsible for SE functional and structural organization.

scholarly journals Sox2 levels configure the WNT response of epiblast progenitors responsible for vertebrate body formation

2020 ◽  
Author(s):  
Robert Blassberg ◽  
Harshil Patel ◽  
Thomas Watson ◽  
Mina Gouti ◽  
Vicki Metzis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Regulatory Element ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Multiple Roles ◽  
Chromatin Interaction ◽  
Pioneer Factor ◽  
Context Specific ◽  
Mesodermal Tissue

AbstractWNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. We provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 acts as a pioneer factor, displacing nucleosomes from regulatory elements with high affinity SOX2 binding sites and recruiting the WNT effector, TCF/β-catenin, to maintain pluripotent gene expression. Reducing SOX2 levels destabilises pluripotency and reconfigures SOX2/TCF/β-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/β-catenin and reveal how context specific responses to a signal are configured by the level of a transcription factor.

scholarly journals Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation

2021 ◽  
Author(s):  
Jiankang Wang ◽  
Masashige Bando ◽  
Katsuhiko Shirahige ◽  
Ryuichiro Nakato
Keyword(s):  
Transcriptional Regulation ◽  
Rna Polymerase Ii ◽  
Binding Sites ◽  
Large Scale ◽  
Gene Activation ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Context Specific ◽  
Comprehensive Characterization

Cohesin, an essential protein complex for chromosome segregation, regulates transcription through a variety of mechanisms. It is not a trivial task to genome-widely assign the diverse cohesin functions. Moreover, the context-specific roles of cohesin-mediated interactions, especially on intragenic regions, have not been thoroughly investigated. Here we performed a comprehensive characterization of cohesin binding sites in several human cell types. We integrated epigenomic, transcriptomic and chromatin interaction data with and without transcriptional stimulation, to explore context-specific functions of intragenic cohesin related to gene activation. We identified a new subset of cohesin binding sites, decreased intragenic cohesin sites (DICs), which have a different function from previously known ones. The intron-enriched DICs were negatively correlated with transcriptional regulation: a subgroup of DICs were related to enhancer markers and paused RNA polymerase II, whereas others contributed to chromatin architecture. We implemented machine learning and successfully isolated DICs with distinct genomic features. We observed DICs in various cell types, including cells from cohesinopathy patients. These results suggest a previously unidentified function of cohesin at intragenic regions for transcription regulation.

scholarly journals Glucocorticoid receptor wields chromatin interactions to tune transcription for cytoskeleton stabilization in podocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hong Wang ◽  
Aiping Duan ◽  
Jing Zhang ◽  
Qi Wang ◽  
Yuexian Xing ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Protective Effect ◽  
Histone Modification ◽  
Regulatory Networks ◽  
Target Gene ◽  
Regulatory Elements ◽  
Chromatin Interactions ◽  
Super Enhancer

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

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