Dynamic nucleosome remodeling mediated by YY1 underlies early mouse development DOI Open Access
M. Sakamoto,

Shusaku Abe,

Yuka Miki

et al.

Genes & Development, Journal Year: 2023, Volume and Issue: 37(13-14), P. 590 - 604

Published: July 1, 2023

Nucleosome positioning can alter the accessibility of DNA-binding proteins to their cognate DNA elements, and thus its precise control is essential for cell identity function. Mammalian preimplantation embryos undergo temporal changes in gene expression potency, suggesting involvement dynamic epigenetic during this developmental phase. However, dynamics nucleosome organization early development are poorly understood. In study, using a low-input MNase-seq method, we show that globally obscure zygotes but becomes well defined subsequent development. Down-regulation chromatin assembly embryonic stem cells partially reverse into zygote-like pattern, possible link between pathway fuzzy nucleosomes zygotes. We also reveal YY1, zinc finger-containing transcription factor expressed upon zygotic genome activation, regulates de novo formation well-positioned arrays at regulatory elements through identifying YY1-binding sites eight-cell embryos. The regions acquire H3K27ac enrichment around morula stages, YY1 depletion impairs morula-to-blastocyst transition. Thus, our study delineates remodeling underlying mechanism mouse

Language: Английский

CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos DOI Creative Commons
Meng Wang, Zhiyuan Chen, Yi Zhang

et al.

The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(22)

Published: Oct. 10, 2022

Abstract Epigenome reprogramming after fertilization enables transcriptionally quiescent maternal and paternal chromatin to acquire a permissive state for subsequent zygotic genome activation (ZGA). H3K27 acetylation (H3K27ac) is well‐established marker of active enhancers promoters. However, dynamics H3K27ac during maternal‐to‐zygotic transition (MZT) in mammalian embryos are not well‐studied. By profiling the allelic landscape mouse MZT, we show that undergoes three waves rapid global transitions between oocyte stage 2‐cell stage. Notably, germinal vesicle zygote globally hyperacetylated, with noncanonical, broad domains correlate H3K4 trimethylation (H3K4me3) open chromatin. marks genomic regions primed including ZGA genes, retrotransposons, alleles imprinted genes. We CBP/p300 HDAC activities play important roles regulating essential preimplantation development. Specifically, acetyltransferase broadly deposits zygotes induce opening condensed at putative ensure proper ZGA. On contrary, HDACs revert canonical safeguard by preventing premature expression developmental In conclusion, coordinated MZT

Language: Английский

Citations

89
Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy DOI Creative Commons
Yanan Qiao, Lei Li,

Song-Hua Hu

et al.

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 13, 2024

Abstract Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric (GABA) GABA/glutamate ratio to inhibit epilepsy. The ameliorated pentetrazol-induced mice. Mechanistically, BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, transcriptionally upregulated SIRT4 glutamate decarboxylase 1 ( GAD1 ). BHB-induced de-carbamylated inactivated dehydrogenase preserve for GABA synthesis, upregulation mouse neuron excitation. BHB administration mice induced pentetrazol. BHB-mediated relief of required high level ratio. These results identified as major metabolite suggested may serve an alternative less toxic agent than KD.

Language: Английский

Citations

23
CBP and Gcn5 drive zygotic genome activation independently of their catalytic activity DOI Creative Commons
Filippo Ciabrelli,

Leily Rabbani,

Francesco Cardamone

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(16)

Published: April 21, 2023

Zygotic genome activation (ZGA) is a crucial step of embryonic development. So far, little known about the role chromatin factors during this process. Here, we used an in vivo RNA interference reverse genetic screen to identify necessary for development Drosophila melanogaster . Our reveals that histone acetyltransferases (HATs) and deacetylases are ZGA regulators. We demonstrate Nejire (CBP/EP300 ortholog) essential acetylation H3 lysine-18 lysine-27, whereas Gcn5 (GCN5/PCAF lysine-9 at ZGA, with these marks being enriched all actively transcribed genes. Nonetheless, HATs activate distinct sets Unexpectedly, individual catalytic dead mutants either or can zygotic transcription transactivate reporter gene vitro. Together, our data as key regulators ZGA.

Language: Английский

Citations

33
Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases DOI Creative Commons
Priyanka Dey Talukdar, Urmi Chatterji

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 13, 2023

Abstract Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and co-activators. Deregulation these regulatory molecules is associated with state transitions, which turn accountable for diverse maladies, including developmental disorders, metabolic most significantly, cancer. A decade back factors, key enablers disease development, were historically viewed as ‘undruggable’; however, intervening years, a wealth literature validated they can be targeted indirectly through transcriptional co-activators, their confederates various physiological molecular processes. These along have ability to initiate modulate genes necessary normal functions, whereby, deregulation such may foster tissue-specific phenotype. Hence, it essential analyze how co-activators specific multilateral processes coordination other factors. The proposed review attempts elaborate an in-depth account involvement regulation, context-specific contributions pathophysiological conditions. This also addresses issue has not been dealt comprehensive manner hopes direct attention towards future research will encompass patient-friendly therapeutic strategies, where drugs targeting enhanced benefits reduced side effects. Additional insights into currently available interventions constraints eventually reveal multitudes advanced targets aiming amelioration good patient prognosis.

Language: Английский

Citations

28
Detection of newly synthesized RNA reveals transcriptional reprogramming during ZGA and a role of Obox3 in totipotency acquisition DOI Creative Commons
M. Sakamoto,

Aoi Ito,

Sayaka Wakayama

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114118 - 114118

Published: April 1, 2024

Zygotic genome activation (ZGA) after fertilization enables the maternal-to-zygotic transition. However, global view of ZGA, particularly at initiation, is incompletely understood. Here, we develop a method to capture and sequence newly synthesized RNA in early mouse embryos, providing transcriptional reprogramming during ZGA. Our data demonstrate that major ZGA gene begins earlier than previously thought. Furthermore, identify set genes activated minor promoters which show enrichment Obox factor motif, find Obox3 or Obox5 overexpression embryonic stem cells activates genes. Notably, expression factors severely impaired somatic cell nuclear transfer (SCNT) restoration corrects profile greatly improves SCNT embryo development. Hence, our study reveals dynamic underscores crucial role facilitating totipotency acquisition.

Language: Английский

Citations

18
Mapping putative enhancers in mouse oocytes and early embryos reveals TCF3/12 as key folliculogenesis regulators DOI
Bofeng Liu, Yuanlin He, Xiaotong Wu

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(6), P. 962 - 974

Published: June 1, 2024

Language: Английский

Citations

13
Systematic evaluation of retroviral LTRs as cis-regulatory elements in mouse embryos DOI Creative Commons
Jian Yang,

Lauryn Cook,

Zhiyuan Chen

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113775 - 113775

Published: Feb. 20, 2024

In mammals, many retrotransposons are de-repressed during zygotic genome activation (ZGA). However, their functions in early development remain elusive largely due to the challenge simultaneously manipulate thousands of retrotransposon insertions embryos. Here, we applied CRISPR interference (CRISPRi) perturb long terminal repeat (LTR) MT2_Mm, a well-known ZGA and totipotency marker that exists ∼2,667 throughout mouse genome. CRISPRi robustly perturbed 2,485 (∼93%) MT2_Mm 1,090 (∼55%) closely related MT2C_Mm 2-cell Remarkably, such perturbation caused downregulation hundreds genes embryonic arrest mostly at morula stage. Mechanistically, MT2 LTRs globally enriched for open chromatin H3K27ac function as promoters/enhancers downstream OBOX/DUX proteins. Thus, not only provide direct evidence support functional importance but also systematically define cis-regulatory embryos by integrating multi-omic analyses.

Language: Английский

Citations

12
Lactate modulates zygotic genome activation through H3K18 lactylation rather than H3K27 acetylation DOI Creative Commons
Yanhua Zhao, Meiting Zhang, Xingwei Huang

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: July 11, 2024

In spite of its essential role in culture media, the precise influence lactate on early mouse embryonic development remains elusive. Previous studies have implicated accumulation medium affecting histone acetylation. Recent research has underscored lactate-derived lactylation as a novel epigenetic modification diverse cellular processes and diseases. Our investigation demonstrated that absence sodium resulted pronounced 2-cell arrest at late G2 phase embryos. RNA-seq analysis revealed significantly impaired maternal-to-zygotic transition (MZT), particularly zygotic gene activation (ZGA). Investigations were conducted employing Cut&Tag assays targeting well-studied acetylation sites, H3K18la H3K27ac, respectively. The findings noticeable reduction under deficiency, this alteration showed significant correlation with changes expression. contrast, H3K27ac exhibited minimal correlation. These results suggest may preferentially through rather than modifications.

Language: Английский

Citations

10
Prmt5 is essential for intestinal stem cell maintenance and homeostasis DOI Creative Commons
Yang Li, Xuewen Li, Chenyi Shi

et al.

Cell Regeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Feb. 5, 2025

Abstract Intestinal homeostasis relies on the continuous renewal of intestinal stem cells (ISCs), which could be epigenetically regulated. While protein arginine methyltransferase 5 (Prmt5) is known to play a key role in multiple organs as an epigenetic modifier, its specific function maintaining remains elucidated. Here, we show that Prmt5 highly expressed mouse crypts. The deletion results ISCs deficiency, ectopic localization Paneth cells, and spontaneous colitis. Mechanistically, sustains high level H3K27ac accumulation by inhibiting Hdac9 expression epithelium, maintains stemness cell-autonomous manner. Notably, inhibition histone deacetylases can rescue both self‐renewal differentiation capacities Prmt5‐depleted ISCs. These findings highlight critical regulator epithelium development tissue homeostasis.

Language: Английский

Citations

2
Chromatin landscape at cis-regulatory elements orchestrates cell fate decisions in early embryogenesis DOI Creative Commons
Francesco Cardamone, Annamaria Piva,

Eva Löser

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 27, 2025

Abstract The establishment of germ layers during early development is crucial for body formation. Drosophila zygote serves as a model investigating these transitions in relation to the chromatin landscape. However, cellular heterogeneity blastoderm embryo poses challenge gaining mechanistic insights. Using 10× Multiome, we simultaneously analyzed vivo epigenomic and transcriptomic states wild-type, E(z)-, CBP-depleted embryos zygotic genome activation at single-cell resolution. We found that pre-zygotic H3K27me3 safeguards tissue-specific gene expression by modulating cis -regulatory elements. Furthermore, demonstrate CBP essential cell fate specification functioning transcriptional activator stabilizing factors binding key developmental genes. Surprisingly, while depletion leads arrest, accessibility continues progress independently through retention stalled RNA Polymerase II. Our study reveals fundamental principles chromatin-mediated regulation establishing maintaining identities embryogenesis.

Language: Английский

Citations

2