A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression DOI Creative Commons
Lorena Hofbauer, Lisa‐Marie Pleyer,

Franziska Reiter

и другие.

Molecular Cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Differential gene transcription enables development and homeostasis in all animals is regulated by two major classes of distal cis-regulatory DNA elements (CREs): enhancers silencers. Although have been thoroughly characterized, the properties mechanisms silencers remain largely unknown. By an unbiased genome-wide functional screen Drosophila melanogaster S2 cells, we discover a class that bind one three factors (TFs) are generally not included chromatin-defined CRE catalogs as they mostly lack detectable accessibility. The silencer-binding TF CG11247, which term Saft, safeguards cell fate decisions vivo functions via highly conserved domain zinc-finger-associated C-terminal (ZAC) corepressor G9a, independently G9a's H3K9-methyltransferase activity. Overall, our identification with unexpected has important implications for understanding future study repressive CREs, well annotation animal genomes.

Язык: Английский

Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation DOI Creative Commons
Bin Zheng, Sarah Gold, Marta Iwanaszko

и другие.

Molecular Cell, Год журнала: 2023, Номер 83(16), С. 2896 - 2910.e4

Опубликована: Июль 12, 2023

Язык: Английский

Процитировано

33
Epigenetic moonlighting: Catalytic-independent functions of histone modifiers in regulating transcription DOI Creative Commons
Marc A. Morgan, Ali Shilatifard

Science Advances, Год журнала: 2023, Номер 9(16)

Опубликована: Апрель 21, 2023

The past three decades have yielded a wealth of information regarding the chromatin regulatory mechanisms that control transcription. “histone code” hypothesis—which posits distinct combinations posttranslational histone modifications are “read” by downstream effector proteins to regulate gene expression—has guided research uncover fundamental relevant many aspects biology. However, recent molecular and genetic studies revealed function histone-modifying enzymes extends independently beyond their catalytic activities. In this review, we highlight original advances in understanding noncatalytic functions modifiers. Many deposited these enzymes—previously considered be required for transcriptional activation—have been demonstrated dispensable expression living organisms. This perspective aims prompt further examination enigmatic inspiring define “epigenetic moonlighting” chromatin-modifying enzymes.

Язык: Английский

Процитировано

30
Stepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription DOI Creative Commons
Chun-Yi Cho, Patrick H. O’Farrell

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 10, 2023

Abstract Binding of transcription factors (TFs) promotes the subsequent recruitment coactivators and preinitiation complexes to initiate eukaryotic transcription, but this time course is usually not visualized. It commonly assumed that recruited eventually co-reside in a higher-order structure, allowing distantly bound TFs activate at core promoters. We use live imaging endogenously tagged proteins, including pioneer TF Zelda, coactivator dBrd4, RNA polymerase II (RNAPII), define cascade events upstream transcriptional initiation early Drosophila embryos. These are sequentially transiently discrete clusters during activation non-histone genes. Zelda acetyltransferase dCBP nucleate dBrd4 clusters, which then trigger pre-transcriptional clustering RNAPII. Subsequent elongation disperses Our results suggest by involves succession distinct biomolecular condensates culminates self-limiting burst transcription.

Язык: Английский

Процитировано

24
HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients DOI Creative Commons
Chiara Mozzetta, Vittorio Sartorelli, Prem Puri

и другие.

Trends in Molecular Medicine, Год журнала: 2024, Номер 30(3), С. 278 - 294

Опубликована: Фев. 26, 2024

Язык: Английский

Процитировано

17
Reshaping transcription and translation dynamics during the awakening of the zygotic genome DOI Creative Commons
Louise Maillard, Pierre Bensidoun, Mounia Lagha

и другие.

Current Opinion in Genetics & Development, Год журнала: 2025, Номер 92, С. 102344 - 102344

Опубликована: Апрель 7, 2025

During the oocyte-to-embryo transition, transcriptome and proteome are dramatically reshaped. This transition entails a shift from maternally inherited mRNAs to newly synthesized transcripts, produced during zygotic genome activation (ZGA). Furthermore, crucial transcription translation selectivity is required for early embryonic development. Studies across various model organisms have revealed conserved cis- trans-regulatory mechanisms dictating regimes by which mRNA proteins this critical phase. In article, we highlight recent technological conceptual advances that deepen our understanding of how tuning both evolves ZGA.

Язык: Английский

Процитировано

1
A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer DOI Creative Commons

Aileen Patricia Szczepanski,

Natsumi Tsuboyama, Huijue Lyu

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 7, 2024

Abstract Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), which functions as robust co-activator of POU2F3, the master transcription factor is critical for both normal and neoplastic tuft cell identity viability. Here, we demonstrate that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements. Loss leads to an inhibition active enhancer nearby genes, such derepression Polycomb-dependent poised are viability differentiation. Mechanistically, depletion results in global redistribution chromatin occupancy SWI/SNF complex, leading significant 3D genome structure change subsequent reprogramming. Our genome-wide CRISPR screen further demonstrates or PTEN-dependent growth defect, highlighting potential role POU2AF2-SWI/SNF axis small lung cancer (SCLC) pathogenesis. Additionally, pharmacological phenocopies terms gene expression alteration decrease SCLC-P subtype cells. Therefore, impeding POU2AF2-mediated represents therapeutic approach human SCLC therapy.

Язык: Английский

Процитировано

9
Inheritance of H3K9 methylation regulates genome architecture in Drosophila early embryos DOI Creative Commons
Nazerke Atinbayeva, Iris Valent, Fides Zenk

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(13), С. 2685 - 2714

Опубликована: Июнь 3, 2024

Abstract Constitutive heterochromatin is essential for transcriptional silencing and genome integrity. The establishment of constitutive in early embryos its role fruitfly development are unknown. Lysine 9 trimethylation histone H3 (H3K9me3) recruitment epigenetic reader, protein 1a (HP1a), hallmarks heterochromatin. Here, we show that H3K9me3 transmitted from the maternal germline to next generation. Maternally inherited H3K9me3, methyltransferases (HMT) depositing it, required organization heterochromatin: lacking H3K9 methylation display de-condensation pericentromeric regions, centromere-centromere de-clustering, mitotic defects, nuclear shape irregularities, resulting embryo lethality. Unexpectedly, quantitative CUT&Tag 4D microscopy measurements HP1a coupled with biophysical modeling revealed H3K9me2/3 largely dispensable recruitment. Instead, main function at this developmental stage drive clustering subsequent compaction. Our results binding absence not sufficient promote proper formation. loss HMTs alters hinders embryonic development.

Язык: Английский

Процитировано

7
Epigenetic inheritance and gene expression regulation in early Drosophila embryos DOI Creative Commons
Filippo Ciabrelli, Nazerke Atinbayeva, Attilio Pane

и другие.

EMBO Reports, Год журнала: 2024, Номер 25(10), С. 4131 - 4152

Опубликована: Сен. 16, 2024

Precise spatiotemporal regulation of gene expression is paramount importance for eukaryotic development. The maternal-to-zygotic transition (MZT) during early embryogenesis in Drosophila involves the gradual replacement maternally contributed mRNAs and proteins by zygotic products. genome transcriptionally activated first 3 hours development, a process known as "zygotic activation" (ZGA), orchestrated activities few pioneer factors. Their decisive role ZGA has been characterized detail, whereas contribution chromatin factors to this historically overlooked. In review, we aim summarize current knowledge how impacts stages embryonic particular, will address following questions: affect transcriptional silencing, architecture promotes integration these processes Remarkably, certain marks can be intergenerationally inherited, their presence embryo becomes critical at later stages. Finally, speculate on possible roles carriers epialleles transgenerational epigenetic inheritance (TEI).

Язык: Английский

Процитировано

6
H3K14ac facilitates the reinstallation of constitutive heterochromatin in Drosophila early embryos by engaging Eggless/SetDB1 DOI Creative Commons
Ruijun Tang,

Mengqi Zhou,

Yuwei Chen

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(33)

Опубликована: Авг. 6, 2024

Constitutive heterochromatin, a fundamental feature of eukaryotic nucleus essential for transposon silencing and genome stability, is rebuilt on various types repetitive DNA in the zygotic during early embryogenesis. However, molecular program underlying this process remains poorly understood. Here, we show that histone H3 lysine 14 acetylation (H3K14ac) engaged reinstallation constitutive heterochromatin

Язык: Английский

Процитировано

5
The KAT module of the SAGA complex maintains the oncogenic gene expression program in MYCN- amplified neuroblastoma DOI Creative Commons
Clare F. Malone, Nathaniel W. Mabe, Alexandra B. Forman

и другие.

Science Advances, Год журнала: 2024, Номер 10(22)

Опубликована: Май 31, 2024

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN -amplified neuroblastoma, a disease of dysregulated development an oncogenic program. We characterized DNA recruitment sites SAGA neuroblastoma and consequences loss lysine acetyltransferase (KAT) activity on histone acetylation gene expression. demonstrate KAT is associated with reduced binding chromatin, suppression MYC/MYCN expression programs, impaired cell cycle progression. Further, showed pharmacologically targetable vitro vivo KAT2A/KAT2B proteolysis targeting chimeric. Our findings expand our understanding histone-modifying complexes maintain state this suggest therapeutic potential inhibitors neuroblastoma.

Язык: Английский

Процитировано

4