Chromatin accessibility in the Drosophila embryo is determined by transcription factor pioneering and enhancer activation

Developmental Cell, Год журнала: 2023, Номер 58(19), С. 1898 - 1916.e9

Опубликована: Авг. 8, 2023

Chromatin accessibility is integral to the process by which transcription factors (TFs) read out cis-regulatory DNA sequences, but it difficult differentiate between TFs that drive and those do not. Deep learning models learn complex sequence rules provide an unprecedented opportunity dissect this problem. Using zygotic genome activation in Drosophila as a model, we analyzed high-resolution TF binding chromatin data with interpretable deep performed genetic validation experiments. We identify hierarchical relationship pioneer Zelda involved axis patterning. consistently pioneers proportional motif affinity, whereas patterning augment contexts where they mediate enhancer activation. conclude occurs two tiers: one through pioneering, makes enhancers accessible not necessarily active, second when correct combination of leads

Язык: Английский

---

Structural dynamics in chromatin unraveling by pioneer transcription factors

Biophysical Reviews, Год журнала: 2024, Номер 16(3), С. 365 - 382

Опубликована: Июнь 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.

Язык: Английский

---

Structural insights into the recognition of native nucleosomes by pioneer transcription factors

Current Opinion in Structural Biology, Год журнала: 2025, Номер 92, С. 103024 - 103024

Опубликована: Март 1, 2025

Язык: Английский

---

Pioneer factors: nature or nurture?

Critical Reviews in Biochemistry and Molecular Biology, Год журнала: 2024, Номер 59(3-4), С. 139 - 153

Опубликована: Май 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.

Язык: Английский

---

Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA

Current Opinion in Structural Biology, Год журнала: 2024, Номер 88, С. 102875 - 102875

Опубликована: Июль 10, 2024

Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially solvent-exposed near entry/exit sites, and frequently interact histones. The extent of TF-histone interactions, turn, depends on motif location nucleosome, type fold, adjacent domains present. interactions phase TF relative nucleosomes, we discuss how these complex surprisingly diverse between nucleosomes contribute function.

Язык: Английский

---

Conservation of symmetry breaking at the level of chromatin accessibility between fly species with unrelated anterior determinants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

Establishing the anterior-posterior body axis is a fundamental process during embryogenesis, and fruit fly, Drosophila melanogaster , provides one of best-known case studies this process. In Drosophila, localized mRNA bicoid serves as anterior determinant (AD). Bicoid engages in concentration-dependent competition with nucleosomes initiates symmetry-breaking along AP by promoting chromatin accessibility at loci transcription factor (TF) genes that are expressed embryo. However, ADs other fly species unrelated structurally distinct, little known about how they function. We addressed question moth Clogmia albipunctata which maternally transcript isoform pair-rule segmentation gene odd-paired egg has been co-opted AD. provide de novo assembly annotation genome describe knockdown zelda maternal affect expression TF-encoding loci. The results these experiments suggest direct roles Cal-Zld opening closing nuclear cleavage cycles show Clogmia's activity promotes early phase zygotic activation homeobrain sloppy-paired conclude dipteran initiate axis-specification level enhancer homologs may serve more widely conserved role initiation pattern formation given their function head development insects.

Язык: Английский

---

Exploring the reciprocity between pioneer factors and development

Development, Год журнала: 2024, Номер 151(13)

Опубликована: Июль 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

Язык: Английский

---

DNA flexibility regulates transcription factor binding to nucleosomes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Cell fate decisions are controlled by sequence-specific transcription factors (TFs), referred to as 'pioneer' factors, that bind their target sites within nucleosomes ('pioneer binding') and thus initiate chromatin opening. However, pioneers just a minority of recognition sequences present in the genome, suggesting local sequence context features may regulate pioneer binding. Here, we developed PIONEAR-seq, highly parallel sequencing-based biochemical assay for high-throughput analysis TF binding on nucleosome positioning sequences. Using characterized 7 human TFs. Comparison based synthetic Widom 601 (W601) model versus three different genomic revealed positional preferences these TFs' (

Язык: Английский

---

Catalytic-dependent and independent functions of the histone acetyltransferase CBP promote pioneer factor-mediated zygotic genome activation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 5, 2024

Summary Immediately after fertilization the genome is transcriptionally quiescent. Maternally encoded pioneer transcription factors reprogram chromatin state and facilitate of zygotic genome. In Drosophila , initiated by factor Zelda. While Zelda-occupied sites are enriched with histone acetylation, a post-translational mark associated active cis -regulatory regions, functional relationship between Zelda acetylation in activation remained unclear. We show that Zelda-mediated recruitment acetyltransferase CBP essential for transcription. catalytic activity necessary release RNA Polymerase II (Pol II) into elongation embryonic development. However, also activates independent through Pol recruitment. Neither nor required pioneering function Our data suggest factor-mediated conserved mechanism to activate but this role separable from restructuring accessibility.

Язык: Английский

---

The maternal-to-zygotic transition: reprogramming of the cytoplasm and nucleus

Nature Reviews Genetics, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 25, 2024

Язык: Английский

---