BRD4 sustains p63 transcriptional program in keratinocytes DOI Creative Commons
Erica Foffi, A. Violante, Rosalba Pecorari

и другие.

Biology Direct, Год журнала: 2024, Номер 19(1)

Опубликована: Ноя. 27, 2024

Here, we investigated the potential interaction between bromodomain-containing protein 4 (BRD4), an established epigenetic modulator and transcriptional coactivator, p63, a member of p53 transcription factor family, essential for epithelial development skin homeostasis. Our protein–protein assays demonstrated strong conserved physical BRD4 family members—p63, p73, p53—suggesting shared binding region among these proteins. While role in cancer through its with has been explored, effects Bromodomain Extra Terminal (BET) inhibitors non-transformed cells, such as keratinocytes, remain largely unknown. functional analyses revealed changes cellular proliferation differentiation keratinocytes depleted either p63 or BRD4, which were further supported by using inhibitor JQ1. Transcriptomic analyses, chromatin immunoprecipitation, RT-qPCR indicated synergistic mechanism regulating keratinocyte-specific target genes, including HK2, FOXM1, EVPL. This study not only highlights complex relationship members but also suggests maintaining keratinocyte functions. findings pave way exploration therapeutic applications treating disorders.

Язык: Английский

CDK7 kinase activity promotes RNA polymerase II promoter escape by facilitating initiation factor release DOI Creative Commons
Taras Velychko,

Eusra Mohammad,

Iván Ferrer-Vicens

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(12), С. 2287 - 2303.e10

Опубликована: Май 30, 2024

Cyclin-dependent kinase 7 (CDK7), part of the general transcription factor TFIIH, promotes gene by phosphorylating C-terminal domain RNA polymerase II (RNA Pol II). Here, we combine rapid CDK7 inhibition with multi-omics analysis to unravel direct functions in human cells. causes retention at promoters, leading decreased initiation and immediate global downregulation transcript synthesis. Elongation, termination, recruitment co-transcriptional factors are not directly affected. Although II, factors, Mediator accumulate complexes can also proceed into bodies without promoter-proximal pausing while retaining Mediator. Further downstream, phosphorylation increases released, allowing elongation an increase velocity. Collectively, activity release from facilitating escape promoter.

Язык: Английский

Процитировано

11
Time is ticking faster for long genes in aging DOI Creative Commons
Sourena Soheili‐Nezhad, Olga Ibáñez-Solé, Ander Izeta

и другие.

Trends in Genetics, Год журнала: 2024, Номер 40(4), С. 299 - 312

Опубликована: Март 21, 2024

Recent studies of aging organisms have identified a systematic phenomenon, characterized by negative correlation between gene length and their expression in various cell types, species, diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) suggest that it may represent bottleneck the machinery thereby significantly contribute to as an etiological factor. review potential links GLTD key processes such DNA damage explore identifying disease modification targets. Notably, Alzheimer's disease, spotlights extremely long synaptic genes at chromosomal fragile sites (CFSs) vulnerability postmitotic damage. is integral element biological aging.

Язык: Английский

Процитировано

10
Single-molecule live imaging of subunit interactions and exchange within cellular regulatory complexes DOI Creative Commons
Thomas G.W. Graham, Claire Dugast‐Darzacq, Gina M. Dailey

и другие.

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

Опубликована: Июнь 25, 2024

Summary Cells are built from vast networks of competing molecular interactions, most which have been impossible to monitor in vivo. We recently devised a new strategy, proximity-assisted photoactivation (PAPA), detect these interactions at single-molecule resolution live cells. Here we apply PAPA visualize the network that regulate central transcription elongation factor P-TEFb. between multiple pairs endogenous proteins, combined with fast tracking (fSMT), revealed inactive P-TEFb within 7SK ribonucleoprotein complex is largely unbound chromatin, this dissociates minutes treatment kinase inhibitor, and heterogeneous ribonucleoproteins (hnRNPs) bind concomitant release. Unlike 7SK-bound P-TEFb, associated coactivator BRD4 exhibited increased binding chromatin. Our results address longstanding questions about key transcriptional regulator demonstrate PAPA-fSMT can probe subunit exchange regulatory complexes

Язык: Английский

Процитировано

7
A Revision of Herpes Simplex Virus Type 1 Transcription: First, Repress; Then, Express DOI Creative Commons
Laura Dunn, Claire Birkenheuer, Joel D. Baines

и другие.

Microorganisms, Год журнала: 2024, Номер 12(2), С. 262 - 262

Опубликована: Янв. 26, 2024

The herpes virus genome bears more than 80 strong transcriptional promoters. Upon entry into the host cell nucleus, these genes are transcribed in an orderly manner, producing five immediate–early (IE) gene products, including ICP0, ICP4, and ICP22, while non-IE mostly silent. IE products necessary for transcription of temporal classes following sequentially as early, leaky late, true late. A recent analysis using precision nuclear run-on followed by deep sequencing (PRO-seq) has revealed important step preceding all HSV-1 transcription. Specifically, proteins ICP4 ICP0 enter with incoming to help preclude nascent antisense, intergenic, sense viral genes. VP16, which is also delivered nucleus upon entry, almost immediately reverses this repression on resulting de novo expression ICP22 further repress early late through different mechanisms before sequential de-repression later infection. This repression, termed transient protein-mediated (TIEMR), precludes unproductive, infection ensure efficient progression cascade.

Язык: Английский

Процитировано

6
Transcriptional elongation control of hypoxic response DOI Creative Commons
Shimaa Soliman, Marta Iwanaszko, Bin Zheng

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(15)

Опубликована: Апрель 2, 2024

The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation gene expression. elongation factor PTEF-b known RNAPII via phosphorylation the C-terminal domain by its cyclin-dependent kinase component, CDK9. However, signal and stress-specific roles various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify characterize CDK9 complex required for transcriptional response hypoxia. Contrary previous reports, our data indicate that a BRD4 but AFF1/4 essential this hypoxic stress response. We demonstrate bromodomains (BET) dispensable at hypoxia-activated genes BET inhibition JQ1 insufficient impair Mechanistically, region Polymerase-Associated Factor-1 Complex (PAF1C) recruitment establish an elongation-competent hypoxia-responsive genes. PAF1C disruption using small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated release. Together, results provide insight into potentially targetable mechanisms control elongation.

Язык: Английский

Процитировано

6
Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges DOI Creative Commons
Sarah Gold, Ali Shilatifard

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(20)

Опубликована: Окт. 14, 2024

As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation the enzyme complexes represent a major frontier therapeutic development. Clinically viable targeting activities of methyltransferases (HKMT) demethylases (HKDMs) have only recently begun emerge following FDA approval EZH2 inhibitor tazemetostat in 2020 remain limited well-studied SET domain-containing HKMTs their opposing HKDMs. These include H3K27 EZH2/EZH1, singular H3K79 methyltransferase DOT1L, H3K4 MLL1/COMPASS well H3K9 H3K36 methyltransferases. They additionally H3K4/9-preferential demethylase LSD1 H3K4-, H3K27-, H3K36-preferential KDM5, KDM6, KDM2 subfamilies, respectively. This Review discusses results recent clinical preclinical studies relevant all these existing therapies. It provides an update on advancements development, more basic molecular understanding, within past 5 years approximately. also offers perspective departs from long-predominant "histone code" metaphor, emphasizing complex-disrupting inhibitors proximity-based approaches rather than catalytic domain outlook future

Язык: Английский

Процитировано

5
LEDGF/p75 promotes transcriptional pausing through preventing SPT5 phosphorylation DOI Creative Commons
Chenghao Guo,

Shuhan Si,

Haitong Fang

и другие.

Science Advances, Год журнала: 2025, Номер 11(3)

Опубликована: Янв. 17, 2025

SPT5 exhibits versatile functions in RNA Pol II promoter proximal pausing, pause release, and elongation metazoans. However, the mechanism underlying functional switch of during early has not been fully understood. Here, we report that phosphorylation site-rich domain (PRD)/CTR1 prion-like (PLD)/CTR2, which are situated adjacent to each other within C-terminal repeat (CTR) SPT5, play pivotal roles pausing elongation, respectively. Our study demonstrates LEDGF/p75 is highly enriched at promoters, especially paused prevents PRD by super complex (SEC). Furthermore, deletion LEDGF IBD leads increased SEC occupancies promoters also release. In sum, our reveals function cooperatively on distinct domains ensure proper transcriptional transition from elongation.

Язык: Английский

Процитировано

0
Basic Epigenetic Mechanisms DOI
James Davie, Hedieh Sattarifard, S Sudhakar

и другие.

Sub-cellular biochemistry/Subcellular biochemistry, Год журнала: 2025, Номер unknown, С. 1 - 49

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
RNA Polymerase II Activity Control of Gene Expression and Involvement in Disease DOI Creative Commons

James C. Kuldell,

Craig D. Kaplan

Journal of Molecular Biology, Год журнала: 2024, Номер 437(1), С. 168770 - 168770

Опубликована: Авг. 28, 2024

Gene expression is dependent on RNA Polymerase II (Pol II) activity in eukaryotes. In addition to determining the rate of synthesis for all protein coding genes, Pol serves as a platform recruitment factors and regulation co-transcriptional events, from processing chromatin modification remodeling. The transcriptome can be shaped by changes kinetics affecting itself or because alterations events that are responsive coupled with transcription. Genetic, biochemical, structural approaches model organisms have revealed critical insights into how works types regulate it. complexity generally increases organismal complexity. this review, we describe fundamental aspects shape gene expression, discuss recent advances elongation regulated altered function linked human disease aging.

Язык: Английский

Процитировано

4
The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release DOI
Zhenning Wang, Aixia Song,

Bolin Tao

и другие.

Molecular Cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

Процитировано

4