Genome-wide interference of chromatin architecture and Mediator in transcriptional bursting and gene network regulation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE241338 | GEO | 2024/06/30
REPOSITORIES: GEO
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Project description:Stochastic transcriptional bursting is now recognized as a universal property of gene expression. While different genes exhibit distinct bursting patterns, the molecular basis for differences in bursting are largely unknown. We have developed and applied a high-throughput-imaging based screening strategy to identify cellular factors and mechanisms that determine the bursting behavior of human genes. Focusing on epigenetic regulators, we find that global acetylation is the strongest acute modulator of burst frequency, size and heterogeneity of bursting. Acetylation similarly affected the Off-time but On-time changes were gene-specific. These effects were not strongly linked to promoter acetylation, which did not correlate with bursting properties and forced promoter acetylation altered bursting for only some genes. Instead, we identified acetylation of the Integrator complex as a key determinant of gene bursting with elevated Integrator acetylation leading to faster bursting. Taken together our results suggest a dominant role of non-histone proteins in determining gene bursting properties and they identify non-epigenetic acetylation of a transcription cofactor as an allosteric modulator of bursting via a pause-release related bursting checkpoint
2024-06-26 | GSE254866 | GEO
Project description:The coactivator p300/CBP regulates genes by facilitating the assembly of transcriptional machinery and by acetylating histones and other factors. However, it remains mostly unclear how both functions of p300 are dynamically coordinated during gene control. Here, we showed that p300 appears to orchestrate two functions through the formation of dynamic co-condensates with certain transcription factors (TFs), which is mediated by the interactions between the TF’s trans-activation domain (TAD) and the intrinsically disordered regions (IDRs) of p300. Co-condensation enables spatially defined, all-or-none activation of p300’s catalytic activity, priming the recruitment of other coactivators including Brd4. We further revealed that co-condensation modulates transcriptional initiation rate and burst duration of target genes, underlying nonlinear and cooperative gene regulatory functions. Intriguingly, such modulation is consistent with how p300 shapes transcriptional bursting kinetics globally. Together, complementary lines of evidence suggest a new p300-mediated gene control mechanism, where TF and p300 co-condensation contributes to transcriptional bursting regulation and cooperative gene control.
2022-02-28 | GSE161958 | GEO
Project description:Cell-to-cell heterogeneity in gene expression can even be observed in the same type of cells, present in a similar environment. Transcriptional bursting is thought to be one of contributing factors to the heterogeneity, but it remains elusive how the kinetic properties of transcriptional bursting (e.g. burst size, burst frequency, and noise induced by transcriptional bursting) are regulated in mammalian cells. To unbiasedly identify genes regulating the kinetic properties of transcriptional bursting, we performed large-scale CRISPR/-Cas9 based screening and functional analysis, and found that Akt/MAPK signaling pathways are involved in the regulation of the kinetic properties of transcriptional bursting.
2020-06-04 | GSE132590 | GEO
Project description:Transcriptional Bursting and Co-bursting Regulation by Steroid Hormone Release Pattern and Transcription Factor Mobility
| PRJNA548190 | ENA
Project description:We investigated modulation of metazoan MED interaction with RNA polymerase II (Pol II) by antagonistic effects of the MED26 subunit and the Cdk8 kinase module (CKM), both of which associate dynamically with MED. Results from in vivo studies point to a general and important role of MED26 in transcription, connected to Pol II recruitment. Analysis of CKM-MED and MED26-MED complexes by cryo-EM and crosslinking-mass spectrometry showed that CKM and MED26 have opposite effects on mMED association with Pol II (blocking and facilitating it, respectively), and revealed that the structural basis for their antagonistic interaction with MED relates to extended intrinsically-disordered regions (IDRs) in MED26 and the CKM subunit MED13 competing for interaction with MED. We found CKM-MED to be the preferred target of nuclear receptors (NRs), whose binding can initiate rearrangements of the MED13 IDR that allow MED26-dependent interaction of CKM-MED with the Pol II carboxy-terminal domain (CTD). Our results suggest that activators might play a critical role independent of MED recruitment, instead “activating” CKM-MED for CTD interaction in a MED26-dependent manner and, thus, controlling the start of preinitiation complex assembly. The presence of an intermediate state in which MED26 and the CTD II can interact with CKM-MED suggests a mechanism for fast, recruitment-independent activation connected to promoter-proximal Pol II pausing, with an activator enabling interaction between the originally inactive CKM-MED and a paused Pol II poised to initiate transcription. We found that CTD interaction with CKM-MED influences the subunit composition of the Tail module and this allostery suggests that the mechanism we propose could apply to non-NR activators targeting Tail subunits.
2024-08-19 | GSE233372 | GEO
Project description:RNA Polymerase II contains a disordered C-terminal domain (CTD) whose length enigmatically correlates with genome size. The CTD is crucial to eukaryotic transcription, yet the functional and evolutionary relevance of this variation remains unclear. Here, we use smFISH, live imaging, and RNA-seq to investigate how CTD length and disorder influence transcription. We find that length modulates the size and frequency of transcriptional bursting. Disorder is highly conserved and mediates CTD-CTD interactions, an ability we show is separable from protein sequence and necessary for efficient transcription. We build a data-driven quantitative model, simulations of which recapitulate experiments and support CTD length promotes initial polymerase recruitment to the promoter but slows down its release from it, and that CTD-CTD interactions enable promoter recruitment of multiple polymerases. Our results reveal how these tunable parameters provide access to a range of transcriptional activity, offering a new perspective for the mechanistic significance of CTD length and disorder in transcription across eukaryotes.
2019-11-16 | GSE140491 | GEO
Project description:This a model from the article:
Complex bursting in pancreatic islets: a potential glycolytic mechanism.
Wierschem K, Bertram R. J Theor Biol
2004 Jun 21;228(4):513-21 15178199
,
Abstract:
The electrical activity of insulin-secreting pancreatic islets of Langerhans is
characterized by bursts of action potentials. Most often this bursting is
periodic, but in some cases it is modulated by an underlying slower rhythm. We
suggest that the modulatory rhythm for this complex bursting pattern is due to
oscillations in glycolysis, while the bursting itself is generated by some other
slow process. To demonstrate this hypothesis, we couple a minimal model of
glycolytic oscillations to a minimal model for activity-dependent bursting in
islets. We show that the combined model can reproduce several complex bursting
patterns from mouse islets published in the literature, and we illustrate how
these complex oscillations are produced through the use of a fast/slow analysis.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Wierschem K, Bertram R. () - version=1.0
The original CellML model was created by:
Ethan Choi
mcho099@aucklanduni.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000682 | BioModels
Project description:Respiratory bursts were observed in A. bisporus. CO2 production and O2 consumption increased up to 3.5 fold during these 3 h bursts while compost temperature increased up to 3 °C. We set out to find which pathways were characteristic for these bursts and the interval between these bursts.
2021-02-24 | GSE124976 | GEO
Project description:Med26 is a subunit of the Human Mediator complex. The Mediator complex is an evolutionarily conserved coregulatory complex that interacts with RNA polymerase II to regulate gene expression. In metazoa, Mediator is composed of some 30 distinct subunits. Mediator exists in multiple, functionally distinct forms that share a common core of subunits and can be distinguished by the presence or absence of a kinase module composed of Med12, Med13, Cdk8, and Cyclin C. In higher eukaryotes, a subset of Mediator complexes is associated with an additional subunit, Med26. This Med26-containing Mediator copurifies from cells with little or no kinase module, but near-stoichiometric Pol II. Evidence suggests that Med26-containing Mediator plays a key role in transcriptional activation however, the mechanism(s) by which Med26 contributes to this process are not known. To identify Med26 target genes, we used Affymetrix U133A plus 2.0 expression arrays to analyze mRNA expression in 293T cells from which Med26 had been depleted by transient transfection by each of three different siRNAs. Three different independent Med26 siRNA knockdowns were compared to a non-targeting control in triplicate, for a total of 12 samples.
2011-08-31 | E-GEOD-28715 | biostudies-arrayexpress
Project description:The chemical sensitivity of urine metabolomics analysis is greatly compromised due to the large amounts of inorganic salts in urine (NaCl, KCl), which are detrimental to analytical instrumentation, e.g. chromatographic columns or mass spectrometers. Traditional desalting approaches applied to urine pretreatment suffer from the chemical losses, which reduce the information depth of analysis. We aimed to test a simple approach for the simultaneous preconcentration and desalting of organic solutes in urine based on the collection of induced bursting bubble aerosols above the surface of urine samples. Bursting bubbles were generated at ambient conditions by feeding gas through an air diffuser at the bottom of diluted (200 times in ultrapure water) urine solution (50-500 mL). Collected aerosols were analyzed by the direct-infusion electrospray ionization mass spectrometry (ESI-MS). The simultaneous preconcentration (ca. 6-12 fold) and desalting (ca. 6-10 fold) of organic solutes in urine was achieved by the bursting bubble sample pretreatment, which allowed ca. 3-times higher number of identified urine metabolites by high-resolution MS analysis. No notable chemical discrimination effects were observed. The increased degree of MS data clustering was demonstrated on the principal component analysis of data sets from the urine of healthy people and from the urine people with renal insufficiency. At least 10 times higher sensitivity of trace drug detection in urine was demonstrated for clenbuterol and salbutamol. Our results indicate the high versatility of bubble bursting as a simple pretreatment approach to enhance the chemical depth and sensitivity of urine analysis.
2016-08-04 | ST000444 | MetabolomicsWorkbench