Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 1, 2024
Language: Английский
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
Critical Reviews in Biochemistry and Molecular Biology, Journal Year: 2024, Volume and Issue: 59(3-4), P. 139 - 153
Published: May 22, 2024
Chromatin is densely packed with nucleosomes, which limits the accessibility of many chromatin-associated proteins. Pioneer factors (PFs) are usually viewed as a special group sequence-specific transcription (TFs) that can recognize nucleosome-embedded motifs, invade compact chromatin, and generate open chromatin regions. Through this process, PFs initiate cascade events play key roles in gene regulation cell differentiation. A current debate field if belong to unique subset TFs intrinsic "pioneering activity", or all have potential function within certain cellular contexts. There also different views regarding feature(s) define pioneering activity. In review, we present evidence from literature related these alternative discuss how potentially reconcile them. It possible both properties, like tight nucleosome binding structural compatibility, conditions, concentration co-factor availability, important for PF function.
Language: Английский
Citations
4
Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15
Published: July 4, 2024
Prostate cancer is one of the most prevalent malignancies and primarily driven by aberrant androgen receptor (AR) signaling. While AR-targeted therapies form cornerstone prostate treatment, they often inadvertently activate compensatory pathways, leading to therapy resistance. This resistance frequently mediated through changes in transcription factor (TF) crosstalk, reshaping gene regulatory programs ultimately weakening treatment efficacy. Consequently, investigating TF interactions has become crucial for understanding mechanisms driving therapy-resistant cancers. Recent evidence highlighted crosstalk between glucocorticoid (GR) AR, demonstrating that GR can induce replacing inactivated thereby becoming a driver disease. In addition this oncogenic role, also been shown act as tumor suppressor cancer. Owing dual role widespread use glucocorticoids adjuvant therapy, it essential understand GR’s actions across different stages development. review, we explore current knowledge cancer, with specific focus on its other TFs. directly indirectly interact variety TFs, these vary significantly depending type cells. By highlighting interactions, aim provide insights guide research development new GR-targeted mitigate harmful effects
Language: Английский
Citations
3
Current Opinion in Cell Biology, Journal Year: 2025, Volume and Issue: 93, P. 102480 - 102480
Published: Feb. 12, 2025
Language: Английский
Citations
0
Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)
Published: March 3, 2025
Abstract Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic epigenetic alterations. Enhancer reprogramming has emerged as pivotal driver carcinogenesis, with cells often relying on aberrant transcriptional programs. The advent high-throughput sequencing technologies provided critical insights into enhancer events their role in malignancy. While targeting enhancers presents promising therapeutic strategy, significant challenges remain. These include the off-target effects enhancer-targeting technologies, complexity redundancy networks, dynamic nature reprogramming, which may contribute to resistance. This review comprehensively encapsulates structural attributes enhancers, delineates mechanisms underlying malignant transformation, evaluates opportunities limitations associated cancer.
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: March 12, 2025
Abstract Understanding how transcription factors regulate organized cellular diversity in developing tissues remains a major challenge due to their pleiotropic functions. We addressed this by monitoring and genetically modulating the activity of PAX3 PAX7 during specification neural progenitor pools embryonic spinal cord. Using mouse models, we show that balance between transcriptional activating repressing functions these is modulated along dorsoventral axis instructive patterning pools. By combining loss-of-function experiments with functional genomics organoids, demonstrate PAX-mediated repression activation rely on distinct cis- regulatory genomic modules. This enables both coexistence dual dorsal cell progenitors specific control two differentiation programs. PAX promotes H3K27me3 deposition at silencers repress ventral identities, while enhancers, they act as pioneer factors, opening modules specify dorsal-most identities. Finally, restricted cells exposed BMP morphogens, ensuring spatial specificity. These findings reveal proteins, morphogen gradients, orchestrate neuronal cord, providing robust framework for subtype specification.
Language: Английский
Citations
0
BioEssays, Journal Year: 2025, Volume and Issue: unknown
Published: April 10, 2025
ABSTRACT Cell plasticity enables the dynamic changes in cell identities necessary for normal development and tissue repair. Induced reprogramming, which leverages this plasticity, holds great promise regenerative medicine personalized therapies. However, success of reprogramming is often impeded by various molecular barriers, such as epigenetic marks, senescence, activation alternative or refractory routes. In review, we examine events that occur within between germ layers adult stem lineages propose overall similarity pre‐existing chromatin accessibility landscape a major determinant efficiency from one type to another. A better understanding regulation control should facilitate new methods strategies improve advance translational research.
Language: Английский
Citations
0
Science Advances, Journal Year: 2025, Volume and Issue: 11(20)
Published: May 16, 2025
Pioneer transcription factors have the unique ability to open chromatin at enhancers implement new cell fates. They also provide epigenetic memory through demethylation of enhancer DNA, but underlying mechanisms remain unclear. We now show that pioneer paired box 7 (PAX7) triggers DNA using two replication-dependent mechanisms, including direct PAX7 interaction with E3 ubiquitin-protein ligase (UHRF1)-DNA methyltransferase 1 (DNMT1) complex is responsible for methylation maintenance. binds UHRF1 and prevents its DNMT1, thus blocking activation enzyme activity. The ten-eleven translocation dioxygenase (TET) demethylases contribute loss methylation. Thus, hijacks block DNMT1 after replication, leading by dilution, process assisted action TET demethylases.
Language: Английский
Citations
0
Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(14), P. 7254 - 7268
Published: June 16, 2023
Pioneer factors are transcription (TFs) that have the unique ability to recognise their target DNA sequences within closed chromatin. Whereas interactions with cognate is similar other TFs, interact chromatin remains poorly understood. Having previously defined modalities of for pioneer factor Pax7, we now used natural isoforms this as well deletion and replacement mutants investigate Pax7 structural requirements interaction opening. We show GL+ isoform has two extra amino acids binding paired domain unable activate melanotrope transcriptome fully a large subset melanotrope-specific enhancers targeted action. This enhancer in primed state rather than being activated, despite having intrinsic transcriptional activity GL- isoform. C-terminal deletions lead same loss ability, reduced recruitments cooperating TF Tpit co-regulators Ash2 BRG1. suggests complex interrelations between domains crucial its opening ability.
Language: Английский
Citations
6
Development, Journal Year: 2024, Volume and Issue: 151(13)
Published: July 1, 2024
ABSTRACT Development is regulated by coordinated changes in gene expression. Control of these expression largely governed the binding transcription factors to specific regulatory elements. However, packaging DNA into chromatin prevents many factors. Pioneer overcome this barrier owing unique properties that enable them bind closed chromatin, promote accessibility and, so doing, mediate additional activate Because properties, pioneer act at top gene-regulatory networks and drive developmental transitions. Despite ability target motifs have cell type-specific occupancy activity. Thus, context clearly shapes pioneer-factor function. Here, we discuss reciprocal interplay between development: how control fate cellular environment influences
Language: Английский
Citations
2