Short activation domains control chromatin association of transcription factors DOI Creative Commons
Vinson B. Fan, Xavier Darzacq, Max V. Staller

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 22, 2024

Abstract Transcription factors regulate gene expression with DNA-binding domains (DBDs) and activation domains. It is generally assumed that DBDs are solely responsible for interacting DNA chromatin. Here, we used single-molecule tracking of transcription in living cells to find short can control the fraction molecules bound Activation high fractions also have longer residence times on Mutations increase activity a transcriptional reporter Reciprocally, mutations decrease bound. These effects were consistent across three DBD classes. Taken together, these results suggest play major role tethering chromatin, challenging traditional view binding

Language: Английский

The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

Citations

237
Intrinsically disordered regions as facilitators of the transcription factor target search DOI
Felix Jonas,

Yoav Navon,

Naama Barkai

et al.

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

Citations

2
PED in 2024: improving the community deposition of structural ensembles for intrinsically disordered proteins DOI Creative Commons
Hamidreza Ghafouri, Tamás Lázár, Alessio Del Conte

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D536 - D544

Published: Oct. 30, 2023

Abstract The Protein Ensemble Database (PED) (URL: https://proteinensemble.org) is the primary resource for depositing structural ensembles of intrinsically disordered proteins. This updated version PED reflects advancements in field, denoting a continual expansion with total 461 entries and 538 ensembles, including those generated without explicit experimental data through novel machine learning (ML) techniques. With this significant increment number few yet-unprecedented new entered database, also determined or refined by electron paramagnetic resonance circular dichroism data. In addition, was enriched several features, deposition service, improved user interface, database cross-referencing options integration 3D-Beacons network—all representing efforts to improve FAIRness database. Foreseeably, will keep growing size expanding types accurate fast ML-based generative models coarse-grained simulations. Therefore, among future efforts, priority be given further develop compatible modeled at level.

Language: Английский

Citations

30
In silico nanoscope to study the interplay of genome organization and transcription regulation DOI Creative Commons
Soundhararajan Gopi, Giovanni B. Brandani, Cheng Tan

et al.

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(6)

Published: March 20, 2025

In eukaryotic genomes, regulated access and communication between cis-regulatory elements (CREs) are necessary for enhancer-mediated transcription of genes. The molecular framework the chromatin organization underlying such remains poorly understood. To better understand it, we develop a multiscale modeling pipeline to build near-atomistic models 200 kb Nanog gene locus in mouse embryonic stem cells comprising nucleosomes, factors, co-activators, RNA polymerase II-mediator complexes. By integrating diverse experimental data, including protein localization, genomic interaction frequencies, cryo-electron microscopy, single-molecule fluorescence studies, our model offers novel insights into its role enhancer-promoter communication. equilibrated by high-performance dynamics simulations span scale ∼350 nm, revealing an experimentally consistent local global transcriptional machinery. Our elucidate that sequence-regulated accessibility facilitates recruitment regulatory proteins exclusively at CREs, guided contrasting nucleosome compared other regions. constructing near-atomic cellular environment, approach provides robust future studies on nuclear compartmentalization, organization, regulation.

Language: Английский

Citations

1
Structural dynamics in chromatin unraveling by pioneer transcription factors DOI Creative Commons

A Orsetti,

Daphne van Oosten,

Roxana-Geanina Vasarhelyi

et al.

Biophysical Reviews, Journal Year: 2024, Volume and Issue: 16(3), P. 365 - 382

Published: June 1, 2024

Pioneer transcription factors are proteins with a dual function. First, they regulate by binding to nucleosome-free DNA regulatory elements. Second, bind while wrapped around histone in the chromatin and mediate opening. The molecular mechanisms that connect two functions yet be discovered. In recent years, pioneer received increased attention mainly because of their crucial role promoting cell fate transitions could used for regenerative therapies. For example, three required induce pluripotency somatic cells, Oct4, Sox2, Klf4 were classified as studied extensively. With this attention, several structures complexes between structural units (nucleosomes) have been resolved experimentally. Furthermore, experimental computational approaches designed study unresolved, key scientific questions: do directly local opening nucleosomes fibers upon binding? And second, how unstructured tails histones impact dynamics involved such conformational transitions? Here we review current knowledge about factor-induced nucleosome process. We discuss what is needed bridge gap static views obtained from dynamic events Finally, propose integrating nuclear magnetic resonance spectroscopy simulations powerful approach studying factor-mediated perhaps small using native sequences.

Language: Английский

Citations

5
Commonly asked questions about transcriptional activation domains DOI Creative Commons
Aditya Udupa,

Sanjana R. Kotha,

Max V. Staller

et al.

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 84, P. 102732 - 102732

Published: Dec. 5, 2023

Eukaryotic transcription factors activate gene expression with their DNA-binding domains and activation domains. bind the genome by recognizing structurally related DNA sequences; they are structured, conserved, predictable from protein sequences. Activation recruit chromatin modifiers, coactivator complexes, or basal transcriptional machinery via diverse protein-protein interactions. have been called independent, modular units, but there many departures modularity, including interactions between these regions overlap in function. Compared to domains, poorly understood because intrinsically disordered, difficult predict This review, organized around commonly asked questions, describes recent progress that field has made understanding sequence features control predicting them sequence.

Language: Английский

Citations

13
Versatile roles of disordered transcription factor effector domains in transcriptional regulation DOI Creative Commons
Rhea R. Datta,

Dilan Akdogan,

Elif B. Tezcan

et al.

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Transcription, a crucial step in the regulation of gene expression, is tightly controlled and involves several essential processes, such as chromatin organization, recognition specific genomic sequences, DNA binding, ultimately recruiting transcriptional machinery to facilitate transcript synthesis. At center this are transcription factors (TFs), which comprise at least one DNA-binding domain (DBD) an effector (ED). Although structure function DBDs have been well studied, our knowledge domains limited. EDs particular importance generating distinct responses between protein members same TF family that similar specificities. The study activity conferred by has traditionally conducted through examining protein-protein interactions. However, recent research uncovered alternative mechanisms regulate formation condensates increase local concentration factors, cofactors, coregulated genes, binding. Here, we provide comprehensive overview known roles factor EDs, with focus on disordered regions. Additionally, emphasize significance intrinsically regions (IDRs) during regulation. We examine underlying establishment maintenance specificity structural properties predominantly EDs. then current understanding these domains, including their physical chemical characteristics, functional roles.

Language: Английский

Citations

0
Single-point mutations in disordered proteins: Linking sequence, ensemble, and function DOI Creative Commons
Eduardo Flores, Nirbhik Acharya, Carlos A. Castañeda

et al.

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 91, P. 102987 - 102987

Published: Feb. 5, 2025

Mutations in genomic DNA often result single-point missense mutations proteins. For folded proteins, the functional effect of these can be understood by their impact on structure. However, intrinsically disordered protein regions (IDRs) remain poorly understood. In IDRs, function depend structural ensemble- collection accessible, interchanging conformations that is encoded amino acid sequence. We argue that, analogously to IDRs alter ensemble, and consequently biological function. To make this argument, we first provide experimental evidence from literature showcasing how affect ensemble dimensions. Then, use data patients show disease-linked occurring can, many cases, significantly IDR ensembles. hope analysis prompts further study disease-linked, IDRs.

Language: Английский

Citations

0
Allovalent scavenging of activation domains in the transcription factor ANAC013 gears transcriptional regulation DOI Creative Commons
Elise Delaforge, Amanda D. Due, Frederik Friis Theisen

et al.

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(4)

Published: Jan. 23, 2025

Transcriptional regulation involves interactions between transcription factors, coregulators, and DNA. Intrinsic disorder is a major player in this regulation, but mechanisms driven by remain elusive. Here, we address molecular communication within the stress-regulating Arabidopsis thaliana factor ANAC013. Through high-throughput screening of ANAC013 for transcriptional activation activity, identify three domains its C-terminal intrinsically disordered region. Two these overlap with acidic islands form dynamic DNA-binding domain are released, not only upon binding target promoter DNA, also nonspecific We show that independently DNA binding, RST (RCD--SRO--TAF4) negative regulator RCD1 (Radical-induced Cell Death1) scavenges two positioned vis-à-vis through allovalent leading to occupation at enhanced affinity. propose an allovalency model where sequentially close both DNA-bound DNA-free states allow efficient regulation. The likely relevant many systems, explaining functional advantage carrying domains.

Language: Английский

Citations

0
Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms DOI
L. Lambourne, Kaia Mattioli, Clarissa Stephanie Santoso

et al.

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0