Power-law behavior of transcriptional bursting regulated by enhancer–promoter communication

Genome Research, Journal Year: 2024, Volume and Issue: 34(1), P. 106 - 118

Published: Jan. 1, 2024

Revealing how transcriptional bursting kinetics are genomically encoded is challenging because genome structures stochastic at the organization level and suggestively linked to gene transcription. To address this challenge, we develop a generic theoretical framework that integrates chromatin dynamics, enhancer–promoter (E-P) communication, gene-state switching study bursting. The theory predicts power law can be general rule quantitatively describe modulations by E-P spatial communication. Specifically, burst frequency size up-regulated communication strength, following laws with positive exponents. Analysis of scaling exponents further reveals preferentially regulated. Bursting down-regulated genomic distance negative power-law exponents, modulation desensitizes large distances. mutual information between (or size) essential characteristics transfer from kinetics. These findings, which in agreement experimental observations, not only reveal fundamental principles but also for understanding cellular decision-making.

Language: Английский

---

Decoding the dynamics of multilayered stochastic antiviral IFN-I responses

Trends in Immunology, Journal Year: 2021, Volume and Issue: 42(9), P. 824 - 839

Published: Aug. 4, 2021

The rise of single-cell technologies has highlighted a massive degree cellular heterogeneity during mammalian interferon (IFN)-I responses.Multilayered stochasticity gives to all-or-nothing decision-making, resulting in tightly regulated fractions responding and nonresponding cells.Mathematical modeling provided crucial insights into the origins complexity IFN-I responses.Mathematical models can be considered as powerful tools dissect predict IFN-I-mediated physiological pathological outcomes. Type I Interferon (IFN-I) responses were first recognized for their role antiviral immunity, but it is now widely appreciated that IFN-Is have many immunomodulatory functions, influencing antitumor responses, autoimmune manifestations, antimicrobial defenses. Given these pivotal roles, may surprising multilayered stochastic events create highly heterogeneous, regulated, decisions. Recently, mathematical nature which we critically evaluate this review. In context, emphasize need innovative combined with further reveal, understand, system conditions relevant plethora diseases. Providing robust line host defense, type (IFN-I; see Glossary) immunity by Isaacs Lindemann [1.Isaacs A. J. Virus interference. I. interferon.Proc. R. Soc. Lond. Ser. B Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar]. addition, are known numerous functions go beyond scope potent roles diseases, microbial infections [2.Musella M. et al.Type-I-interferons infection cancer: unanticipated dynamics therapeutic implications.Oncoimmunology. 2017; 6e1314424Crossref Scopus (41) Scholar, 3.Psarras al.Type interferon-mediated diseases: pathogenesis, diagnosis targeted therapy.Rheumatology. 56: 1662-1675PubMed 4.McNab F. interferons infectious disease.Nat. Rev. Immunol. 2015; 15: 87-103Crossref (852) expression regulation been extensively studied mammals, important molecular regulators characterized (Box 1; reviewed [4.McNab 5.Ivashkiv L.B. Donlin L.T. Regulation i responses.Nat. 2014; 14: 36-49Crossref (1323) 6.Mesev E.V. al.Decoding III signalling viral infection.Nat. Microbiol. 2019; 4: 914-924Crossref (92) Scholar]). Population-averaged measurements generated not only wealth knowledge on regulation, also contradictory results remain hard interpret or understand [7.Drayman N. al.HSV-1 analysis reveals activation anti-viral developmental programs distinct sub-populations.Elife. 8: 1-25Crossref (37) Over past few years, an overwhelming wave data changed dogma how systemic immune generated, challenging traditional assumption all cells given lineage display nearly identical behaviors upon stimulation.Box 1Basics responsesIFN-I-mediated provide defense against viruses other invading pathogens [5.Ivashkiv long history coevolution, hardwired within genomes complex. This ensures IFN needed avoid tissue damage potential autoimmunity [100.Trinchieri G. interferon: friend foe?.J. Exp. Med. 2010; 207: 2053-2063Crossref (579) constitute largest class, comprising IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-ω humans. Different subtypes differential binding affinities receptors (reviewed [101.Pestka S. interferons: 50 years after discovery, there much more learn.J. Chem. 2007; 282: 20047-20051Abstract Full Text PDF (256) Consequently, various outcomes, involving antiviral, immunomodulatory, antiproliferative activity, occur [102.Jaitin D.A. al.Inquiring action (IFNs): IFN- 2 mutant enhanced affinity IFNAR1 functionally similar IFN-beta.Mol. Cell. 2006; 26: 1888-1897Crossref (167) 103.Kalie E. al.The stability ternary interferon-receptor complex rather than individual subunits dictates biological activities.J. 2008; 283: 32925-32936Abstract (80) 104.Moraga al.Receptor density key Alpha2/Beta activities.Mol. 2009; 29: 4778-4787Crossref (65) production elicited almost every cell type, simply because evolved successfully infect type. Similarly, IFN-α/β (IFNARs) constitutively expressed cells, allowing acquire state.The prevalent pathway induction initiated when viral, xenogeneic, autologous nucleic acids cytosolic receptors, RNA helicases, retinoic acid-inducible gene (RIG-I, melanoma differentiation-associated 5 (MDA5). Upon activation, RIG-I-like (RLRs), initiate signaling cascade leading translocation transcription factor regulatory 3 (IRF3), induces Via Toll-like (TLR3/7/8/9) endosomes, phagocytic such macrophages, dendritic pDCs, recognize endosomal acids, IRF7, similarly IRF3 [105.Honda K. inteferon family factors.Immunity. 25: 349-360Abstract (810) via autocrine IFN-α IFN-β predominantly, upregulation IRF7 components Scholar].Upon vast production, diffuse subsequently bind IFNARs neighboring cells. IFNAR1-associated protein tyrosine kinase (Tyk2) IFNAR2-associated kinases Janus 1 (JAK1) regulate phosphorylation different signal transducer activator (STAT) proteins Activated STAT homo- heterodimerize translocate nucleus, where they promote several target genes, IFN-stimulated genes (ISGs), including directly activate nuclear factor-κB (NF-κB) pathways, additional proinflammatory cytokines, thereby promoting population-wide both infected uninfected state. Improving experimental approaches, use fluorescently tagged reporter mice, single-mRNA molecule situ hybridization, quantitative PCR, sequencing (scRNA-seq), microfluidic revealed along multiple layers stochasticity, turn yield 8.Steuerman Y. al.Dissection Influenza vivo sequencing.Cell Syst. 2018; 6: 679-691Abstract (64) 9.Zanini al.Single-cell transcriptional flavivirus infection.Elife. 7e32942Crossref (55) 10.Russell A.B. al.Extreme influenza virus single cells.Elife. 7: 1-26Crossref (91) 11.Shnayder al.Defining landscape cytomegalovirus latency sequencing.MBio. 9e00013-18Crossref (78) 12.Hu al.Role cell-to-cell variability activating positive feedback response human cells.PLoS ONE. 2011; 6e16614Crossref (28) 13.Patil shows paracrine responder shapes interferon-β infection.Sci. Signal. 1-13Crossref (39) 14.Rand U. al.Multi-layered propagation shape type-l response.Mol. 2012; (86) 15.Zhao al.Stochastic gene.PLoS 10e1001249Crossref (77) 16.Shalek A.K. RNA-seq dynamic control variation.Nature. 510: 363-369Crossref (506) 17.Wimmers interferon-alpha plasmacytoid cells.Nat. Commun. 9: 3317Crossref (46) scRNA-seq allowed examination virus–host interactions variety vitro systems, again highlighting extreme cell–cell pathways [8.Steuerman conditions, small begin producing infection, vitro, ex vivo, Scholar,13.Patil Scholar,16.Shalek 18.Van Eyndhoven L.C. al.Phenotypical diversification early IFNα-producing using droplet-based microfluidics.Front. 2021; 12: 1592Crossref (0) 19.Bauer al.Cutting edge: spleen restricted subpopulation exhibiting specific modulatory transcriptome signature.J. 2016; 196: 4447-4451Crossref (19) Of note, responders, referred 'precocious cells' 'early cells', proposed arise from phenomenon observed cytokines Scholar,20.Shalek transcriptomics bimodality splicing cells.Nature. 2013; 498: 236-240Crossref (706) 21.Bhushal al.Cell polarization epigenetic status heterogeneous intestinal epithelial cells.Front. 671Crossref 22.Doǧanay determinant stochastic: IFNB1 expression.Integr. 857-867Crossref turn, prime surrounding enhance recognition, process larger fraction so-called second responders; this, second, profound [13.Patil Scholar,22.Doǧanay 23.Sen al.Innate homologous rotavirus villous epithelium at resolution.Proc. Natl. Acad. 109: 20667-20672Crossref 24.Scheu al.Visualization IFNβ versus conventional under stimulation vivo.Proc. 105: 20416-20421Crossref 25.O'Neal J.T. al.West Nile virus-inclusive cells.J. Virol. 93e01778-18Crossref (16) 26.Apostolou Thanos D. NF-κB-dependent interchromosomal associations mediating monoallelic expression.Cell. 134: 85-96Abstract (178) 27.Talemi S.R. Höfer T. Antiviral resolution.Immunol. 285: 72-80Crossref (8) 28.Hu al.Chromosome-specific noisy virus-infected primary cells.Nucleic Acids Res. 35: 5232-5241Crossref (50) Lastly, most despite being and/or activated signaling, will start over course due inflammation, called nonresponders [17.Wimmers Scholar,18.Van evidently and, therefore, apply advanced technologies, ways large amounts systems immunology data, magnified. Mathematical enable scientists smaller pieces easier understand. Additionally, simulations generate hypothetical outcomes validated improve quality models. Moreover, used certain interventional studies. For system, regarding address These enabled better heterogenous decisions made infection. Here, brief overview arising virus-induced causes heterogeneity, leads three aforementioned fates, aid interpretation, understanding, prediction Altogether, serve reveal manner surpass alone. As become evident, its extensively. Cellular deemed result events, divided approximately distinct, intertwined (Figure 1) Scholar,14.Rand Each layer originates chronologically involves biological, biochemical, biophysical processes. variable terms onset time, load, expression, response, so on. Even before infected, originate random distribution particles encounter [29.Cohen E.M. Kobiler O. Gene correlates number herpes initiating Pathog. 12e1006082Crossref (21) genetic population lead even variation, some less successful establishing [30.Lauring A.S. mutational robustness evolution.Nat. 11: 327-336Crossref (210) Scholar,31.Stern al.Costs benefits viruses.Cell Rep. 1026-1036Abstract (34) Subsequently, vary replication efficiency inside host, differences subsequent secretion [22.Doǧanay Scholar,32.Killip M.J. al.Failure promoter paramyxovirus lacking antagonist.Virology. 415: 39-46Crossref (32) Finally, recent report showed recognition live cytomegalovirus-infected mounted (pDCs) compared self-recognition mimetics [33.Yun T.J. al.Human mount cells.Sci. 6eabc7302Crossref dictating involve state time [34.Drayman al.Dynamic proteomics simplex infection.MBio. 8e01612-17Crossref (17) arises deterministic processes (e.g., cycle) processes, noise) [35.Loewer Lahav We individuals: consequences non-genetic cells.Curr. Opin. Genet. Dev. 21: 753-758Crossref (49) 36.Kellogg R.A. Tay Noise facilitates inputs.Cell. 160: 381-392Abstract 37.Mudla al.Cell-cycle-gated mediates desensitization stimulation.Elife. 2020; 1-23Crossref It thought intrinsic noise biochemical reactions, whereas extrinsic fluctuations involved generating [38.Dey S.S. al.Orthogonal mean variance features genomic loci.Mol. 806Crossr

Language: Английский

---

Transcription factor binding kinetics and transcriptional bursting: What do we really know?

Current Opinion in Structural Biology, Journal Year: 2021, Volume and Issue: 71, P. 239 - 248

Published: Sept. 2, 2021

Language: Английский

---

STREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 20, 2022

Abstract Transcription is a dynamic process. To detect the relationship among protein clusters of RNA polymerase II and coactivators, gene loci, transcriptional activity, we insert an MS2 repeat, TetO inteins with selection marker just downstream transcription start site. By optimizing individual elements, develop Spliced REpeAt, INtein sandwiched reporter Gene tag (STREAMING-tag) system. Clusters BRD4 are observed proximal to site Nanog when transcribed in mouse embryonic stem cells. In contrast, MED19 MED22 tend be located near site, even without activity. Thus, STREAMING-tag system reveals spatiotemporal relationships between activity gene. This powerful tool useful for quantitatively understanding regulation living

Language: Английский

---

Protein translation rate determines neocortical neuron fate

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 7, 2024

The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as determinant cortical neuron identity. We find specific upregulation synthesis in the progenitors later-born neurons show that translation rates concomitantly half-lives are inherent features subtypes. small molecule screening, identify Ire1α regulator Satb2 neuronal polarity. developing brain, regulates global rates, coordinates ribosome traffic, eIF4A1. Furthermore, demonstrate mRNA requires eIF4A1 helicase activity towards its 5'-untranslated region. Altogether, is generated by mechanisms operating beyond transcription, with Ire1α-safeguarded proteostasis serving essential brain development.

Language: Английский

---

Transcription-coupled changes in genomic region proximities during transcriptional bursting

Science Advances, Journal Year: 2024, Volume and Issue: 10(49)

Published: Dec. 6, 2024

The orchestration of our genes heavily relies on coordinated communication between enhancers and promoters, yet the mechanisms behind this dynamic interplay during active transcription remain unclear. Here, we investigated enhancer-promoter (E-P) interactions in relation to transcriptional bursting mouse embryonic stem cells using sequential DNA/RNA/immunofluorescence–fluorescence situ hybridization analyses. Our data reveal that state specific is characterized by proximities different genomic regions accumulation regulatory factors. Mathematical simulations suggest an increase local viscosity could potentially contribute stabilizing duration these E-P proximities. study provides insights into association among proximity, protein accumulation, dynamics, paving way for a more nuanced understanding gene-specific mechanisms.

Language: Английский

---

Compound bursting behaviors in a forced Mathieu-van der Pol-Duffing system

Chaos Solitons & Fractals, Journal Year: 2021, Volume and Issue: 147, P. 110967 - 110967

Published: April 24, 2021

Language: Английский

---

Mechanical stimulation from the surrounding tissue activates mitochondrial energy metabolism in Drosophila differentiating germ cells

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(21), P. 2249 - 2260.e9

Published: Aug. 29, 2023

Language: Английский

---

3D chromatin architecture, BRD4, and Mediator have distinct roles in regulating genome-wide transcriptional bursting and gene network

Science Advances, Journal Year: 2024, Volume and Issue: 10(32)

Published: Aug. 9, 2024

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses transcriptome-wide have focused on role cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data infer dynamics under multiple conditions identify possible molecular mechanisms. found Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC burst size, while cohesin Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects levels among these perturbations, acute depletion MED26 had most profound impact entire regulatory network, acting downstream chromatin spatial architecture without affecting TATA box-binding (TBP) recruitment. These results indicate later steps in initiation bursts primary nodes for integrating networks single cells.

Language: Английский

---

Priestia megaterium cells are primed for surviving lethal doses of antibiotics and chemical stress

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 8, 2025

Antibiotic resistant infections kill millions worldwide yearly. However, a key factor in recurrent is antibiotic persisters. Persisters are not inherently antibiotic-resistant but can withstand exposure by entering non-dividing state. This tolerance often results prolonged usage, increasing the likelihood of developing strains. Here, we show existence "primed cells" Gram-positive bacterium Priestia megaterium, formerly known as Bacillus megaterium. These cells pre-adapted to become persisters prior lethal stress. Remarkably, this prepared state passed down through multiple generations via epigenetic memory, enhancing survival against antibiotics and other chemical Previously, two distinct types were proposed: Type I II, formed during stationary log phases, respectively. our findings reveal that primed contribute an increase transition with no evidence supporting phenotypes between II

Language: Английский

---