CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos

The EMBO Journal, Год журнала: 2022, Номер 41(22)

Опубликована: Окт. 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

Язык: Английский

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Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy

Cell Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Фев. 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.

Язык: Английский

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Detection of newly synthesized RNA reveals transcriptional reprogramming during ZGA and a role of Obox3 in totipotency acquisition

Cell Reports, Год журнала: 2024, Номер 43(4), С. 114118 - 114118

Опубликована: Апрель 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.

Язык: Английский

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CBP and Gcn5 drive zygotic genome activation independently of their catalytic activity

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

Опубликована: Апрель 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.

Язык: Английский

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Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Ноя. 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.

Язык: Английский

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Systematic evaluation of retroviral LTRs as cis-regulatory elements in mouse embryos

Cell Reports, Год журнала: 2024, Номер 43(3), С. 113775 - 113775

Опубликована: Фев. 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.

Язык: Английский

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Mapping putative enhancers in mouse oocytes and early embryos reveals TCF3/12 as key folliculogenesis regulators

Nature Cell Biology, Год журнала: 2024, Номер 26(6), С. 962 - 974

Опубликована: Июнь 1, 2024

Язык: Английский

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SETD1B-mediated broad H3K4me3 controls proper temporal patterns of gene expression critical for spermatid development

Cell Research, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Abstract Epigenetic programming governs cell fate determination during development through intricately controlling sequential gene activation and repression. Although H3K4me3 is widely recognized as a hallmark of activation, its role in modulating transcription output timing within continuously developing system remains poorly understood. In this study, we provide detailed characterization the epigenomic landscapes male germ cells. We identified thousands spermatid-specific broad domains regulated by SETD1B-RFX2 axis, representing previously underappreciated form H3K4me3. These domains, overlapping with H3K27ac-marked enhancers promoters, play critical roles orchestrating robust accurate temporal control expression. Mechanistically, these compete effectively regular for transcriptional machinery, thereby ensuring levels precise master expression mouse spermiogenesis. Disruption mechanism compromises accuracy dosage timing, ultimately impairing Additionally, unveil remarkable changes distribution heterochromatin marks, including H3K27me3 H3K9me2, mitosis-to-meiosis transition completion meiotic recombination, which closely correlates silencing. This work underscores highly orchestrated epigenetic regulation spermatogenesis, highlighting unrecognized Setd1b formation control, provides an invaluable resource future studies toward elucidation spermatogenesis.

Язык: Английский

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Epigenome dynamics in early mammalian embryogenesis

Nature Reviews Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

Язык: Английский

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Reshaping transcription and translation dynamics during the awakening of the zygotic genome

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

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