Mapping the Dynamics of the Glucocorticoid Receptor within the Nuclear Landscape

Stortz, Martín; Presman, Diego M.; Bruno, Luciana; Annibale, Paolo; Dansey, M. Virginia; Burton, Gerardo; Gratton, Enrico; Pecci, Adalı́; Levi, Valeria

doi:10.1038/s41598-017-06676-0

Cited by 36 publications

(48 citation statements)

References 83 publications

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“…Transcriptional regulation by nuclear receptors is a dynamic process that is gene and cell specific (43,44). This phenomenon has been described according to 2 temporal scales: fast protein-DNA interaction (ms) accessible through single-living-cell fluorescent approaches (45), and global bursts of a whole receptor population binding via ChIP (40). In the current study, we demonstrate that MR is recruited onto the PER1 promoter in a dynamic and cyclical manner.…”

Section: Discussionmentioning

confidence: 50%

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

et al. 2018

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Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling. Here, we decipher the transcriptional regulatory mechanisms that underlie selective effects of MRs and GRs on shared genomic targets in a human renal cellular model. Kinetic, serial, and sequential chromatin immunoprecipitation approaches were performed on the period circadian protein 1 ( PER1) target gene, providing evidence that both receptors dynamically and cyclically interact at the same target promoter in a specific and distinct transcriptional signature. During this process, both receptors regulate PER1 gene by binding as homo- or heterodimers to the same promoter region. Our results suggest a novel level of MR-GR target gene regulation, which should be considered for a better and integrated understanding of corticosteroid-related pathophysiology.-Le Billan, F., Amazit, L., Bleakley, K., Xue, Q.-Y., Pussard, E., Lhadj, C., Kolkhof, P., Viengchareun, S., Fagart, J., Lombès, M. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

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Section: Discussionmentioning

confidence: 50%

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

et al. 2018

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“…Critical efforts are required to investigate whether the slow(er) stops seen in SMT are matched exclusively to specific interactions with chromatin. Alternatively, a sub-population of these “stops” could correspond to microscopic regions in the nucleus where diffusion is severely impaired, or transient interaction with “clustered” structures such as foci observed for GR 44 , or another hitherto unknown mechanism.…”

Section: Discussionmentioning

confidence: 99%

Power-law behaviour of transcription factor dynamics at the single-molecule level implies a continuum affinity model

Garcia

Fettweis

Presman

et al. 2019

Preprint

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30Single-molecule tracking allows the study of transcription factor dynamics in the 31 nucleus, giving important information regarding the search and binding behavior of 32 these proteins with chromatin in vivo. However, these experiments suffer from 33 limitations due to photobleaching of the tracked protein and assumptions about the 34 exponential behavior required for data interpretation, potentially leading to serious 35 artifacts. Here, we developed an improved method to account for photobleaching 36 effects, theory-based models to accurately describe transcription factor dynamics, and 37 an unbiased model selection approach to determine the best predicting model. A new 38 biological interpretation of transcriptional regulation emerges from the proposed models 39 wherein transcription factor searching and binding on the DNA results in a broad 40 distribution of binding affinities and accounts for the power-law behavior of transcription 41 factor residence times. 42

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“…Figure 3a,b show the mean, normalized autocorrelation functions (ACF) obtained for Oct4-YPet and Sox2-YPet in undifferentiated and early-differentiated ES cells. The ACF curves could be interpreted with a model that includes the diffusion of the proteins and their interactions with chromatin targets in two distinct temporal windows 15,18,36 . The fitting of the model to the experimental data provides relevant information on how TFs distribute within the nuclear space.…”

Section: Dynamical Distribution Of Tfs In the Nucleus At The Onset Ofmentioning

confidence: 99%

“…Furthermore, many transcription-related biomolecules partition into compartments which are not enclosed by membranes 16 and contribute to buffer the amount of molecules in the nucleoplasm 17,18 . Very recently, it has been proposed that a liquid-liquid phase separation process drives the formation of many nuclear compartments 19 that may play important roles in the local remodeling of chromatin 20 and genes activation 21,22 finally impacting on the transcriptional output 23 .…”

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confidence: 99%

Dynamical reorganization of the pluripotency transcription factors Oct4 and Sox2 during early differentiation of embryonic stem cells

Verneri

Echegaray

Oses

et al. 2020

Sci Rep

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Pluripotency maintenance requires transcription factors (TFs) that induce genes necessary to preserve the undifferentiated state and repress others involved in differentiation. Recent observations support that the heterogeneous distribution of TFs in the nucleus impacts on gene expression. Thus, it is essential to explore how TFs dynamically organize to fully understand their role in transcription regulation. Here, we examine the distribution of pluripotency TFs Oct4 and Sox2 in the nucleus of embryonic stem (ES) cells and inquire whether their organization changes during early differentiation stages preceding their downregulation. Using ES cells expressing Oct4-YPet or Sox2-YPet, we show that Oct4 and Sox2 partition between nucleoplasm and a few chromatin-dense foci which restructure after inducing differentiation by 2i/LIF withdrawal. Fluorescence correlation spectroscopy showed distinct changes in Oct4 and Sox2 dynamics after differentiation induction. Specifically, we detected an impairment of Oct4-chromatin interactions whereas Sox2 only showed slight variations in its shortlived, and probably more unspecific, interactions with chromatin. Our results reveal that differentiation cues trigger early changes of Oct4 and Sox2 nuclear distributions that also include modifications in TF-chromatin interactions. This dynamical reorganization precedes Oct4 and Sox2 downregulation and may contribute to modulate their function at early differentiation stages.

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Mapping the Dynamics of the Glucocorticoid Receptor within the Nuclear Landscape

Cited by 36 publications

References 83 publications

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

Power-law behaviour of transcription factor dynamics at the single-molecule level implies a continuum affinity model

Dynamical reorganization of the pluripotency transcription factors Oct4 and Sox2 during early differentiation of embryonic stem cells

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