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Nuclear class 3 PI3K co-activates fasting-specific chromatin remodeling

ABSTRACT: Transcriptional remodeling in fasting assures metabolic adaptation that provides health benefits across species1-5. While the regulators of transcription and chromatin organization in fasting are known6-10, how lack of nutrients impacts RNA Pol II (RNAPII) and epigenetic writers remains unclear. Surprisingly, we find that class 3 Phosphatidyl inositol-3 kinase (PI3K-3) lipid kinase, a master regulator of autophagy11, is present at chromatin where it co-activates epigenetic writers for transcriptional activation. To this end, the chromatin distribution of PI3K-3 largely overlapped with transcriptionally engaged RNAPII phosphorylated on Ser5 (RNAPII-S5p) and Setd1a/COMPASS, the transcription activating H3K4me3 methyltransferase complex12. Mechanistically, nuclear PI3K-3 interacted with RNAPII and the Set1a/COMPASS transcriptional complexes and facilitated their binding. Accordingly, PI3K-3 deletion resulted in lower H3K4me3 and RNAPII-S5p enrichment at selective loci. Conversely, PI3K-3 overexpression co-activated acetyltransferase p300/CBP while chromatin targeting of PI3K-3 promoted H3K4me3 deposition. In starved cells, PI3K-3 was needed for the transcriptional induction of autophagy-related genes, and in fasted liver, it was critical for metabolic shift, such as ketogenesis and lipid degradation. Thus, PI3K-3 couples nutrient availability to chromatin remodeling enabling adaptive transcriptional activation during nutrient stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322778 | GEO | 2026/06/02

REPOSITORIES: GEO

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Nuclear class 3 PI3K co-activates fasting-specific chromatin remodeling

Project description:Transcriptional remodeling in fasting assures metabolic adaptation that provides health benefits across species1-5. While the regulators of transcription and chromatin organization in fasting are known6-10, how lack of nutrients impacts RNA Pol II (RNAPII) and epigenetic writers remains unclear. Surprisingly, we find that class 3 Phosphatidyl inositol-3 kinase (PI3K-3) lipid kinase, a master regulator of autophagy11, is present at chromatin where it co-activates epigenetic writers for transcriptional activation. To this end, the chromatin distribution of PI3K-3 largely overlapped with transcriptionally engaged RNAPII phosphorylated on Ser5 (RNAPII-S5p) and Setd1a/COMPASS, the transcription activating H3K4me3 methyltransferase complex12. Mechanistically, nuclear PI3K-3 interacted with RNAPII and the Set1a/COMPASS transcriptional complexes and facilitated their binding. Accordingly, PI3K-3 deletion resulted in lower H3K4me3 and RNAPII-S5p enrichment at selective loci. Conversely, PI3K-3 overexpression co-activated acetyltransferase p300/CBP while chromatin targeting of PI3K-3 promoted H3K4me3 deposition. In starved cells, PI3K-3 was needed for the transcriptional induction of autophagy-related genes, and in fasted liver, it was critical for metabolic shift, such as ketogenesis and lipid degradation. Thus, PI3K-3 couples nutrient availability to chromatin remodeling enabling adaptive transcriptional activation during nutrient stress.

2026-06-02 | GSE320350 | GEO

Nuclear class 3 PI3K co-activates fasting-specific chromatin remodeling

Project description:Transcriptional remodeling is essential for stress adaptation such as in fasting. While the core transcriptional machinery and its regulators are known, how information regarding energy availability is relayed to transcriptional complexes remains unclear. Surprisingly, we find that class 3 Phosphatidyl inositol-3 kinase (PI3K-3) lipid kinase, a master regulator of cytosolic autophagy, co-activates epigenetic writers for fasting-induced transcription. To this end, chromatin distribution of PI3K-3 significantly overlapped with transcriptionally engaged RNA Pol II phosphorylated on Ser5 (RNAPII-S5p) and transcriptionally permissive H3K4me3. Mechanistically, nuclear PI3K-3 interacted with both RNAPII and the Set1a/COMPASS methyltransferase of H4K4me3. Moreover, decreased binding between RNAPII and Set1a/COMPASS was found in PI3K-3 depleted cells. Accordingly, PI3K-3 deletion led to lower H3K4me3 and RNAPII-S5p enrichment at selective loci. Conversely, PI3K-3 overexpression co-activated acetyltransferase p300/CBP in luciferase assays while its chromatin targeting promoted H3K4me3 deposition. In starved cells, PI3K-3 induced transcription of autophagy-related genes, and in fasted liver, it was critical for transcriptional remodeling of metabolism, such as activation of lipid degradation. Thus, PI3K-3 couples nutrient availability to chromatin remodeling for transcriptional activation, enabling metabolic adaptation in fasting.

2026-06-02 | GSE290680 | GEO

Nuclear class 3 PI3K co-activates fasting-specific chromatin remodeling

2026-06-02 | GSE290682 | GEO

Nuclear class 3 PI3K co-activates fasting-specific chromatin remodeling

2026-06-02 | GSE290681 | GEO

H3K4me3 regulates RNA polymerase II promoter-proximal pause-release

Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, by using mouse embryonic stem cells (mESCs) as a model system, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to complete loss of all H3K4 methylation. H3K4me3 turnover occurs more rapidly than H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Surprisingly, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. Notably, we show that H3K4me3 is required for the recruitment of the Integrator Complex Subunit 11 (INTS11), which is essential for the eviction of paused RNAPII and transcriptional elongation. Thus, our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.

2023-02-10 | PXD039176 | Pride

Histone H3 lysine 4 trimethylation regulates RNA polymerase II promoter-proximal pause-release

Project description:Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and proposed to regulate transcription initiation. However, redundant functions of the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation of the specific role of H3K4me3 in transcriptional regulation. Here, we show that acute ablation of shared subunits of the SET1/COMPASS complexes leads to complete loss of all H3K4 methylation. H3K4me3 turnover occurs more rapidly than H3K4me1 and H3K4me2 and is dependent on KDM5 demethylases. Surprisingly, acute loss of H3K4me3 does not have detectable effects on transcriptional initiation but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II (RNAPII) pausing and slower elongation. Our study demonstrates a distinct role for H3K4me3 in transcriptional pause-release and elongation rather than transcriptional initiation.

2023-03-14 | PXD028858 | Pride

ZWC Complex-Mediated SPT5 Phosphorylation Suppresses Divergent Antisense RNA Transcription at the Active Gene Promoters [ChIP-Seq]

Project description:Purpose: The goals of this study are to understand the mechanistic roles of newly identified ZWC chromatin complex on the regulation of transcriptional process in actively transcribed genes. The novel ZWC complex is composed of ZC3H4, WDR82, and casein kinase II (CK2) subunits. Methods: Two biological replicates of ChIP-seq data for ZC3H4, WDR82, CK2, and SPT5 were generated from HEK293 cells. And one replicate of ChIP-seq data for RNAPII, H3K4me3, H3K27me3, and H3K36me3 was generated in HEK293 cells. Two biological replicates of ChIP-seq data were generated for RNAPII, S5p RNAPII, S2p RNAPII, SPT5, H3K4me3, H3K36me3, H3K27me3 after HEK293 cells were treated with control or ZC3H4 siRNAs. Results: The ZWC complex preferentially localizes at TSSs of active genes through the direct interactions of ZC3H4 and WDR82 subunits with S5p RNAPII CTD. ZC3H4 depletion leads to increased divergent antisense transcription. Conclusion: Our study provides evidence that the newly identified ZWC-DSIF axis regulates the direction of transcription during the transition from early to productive elongation

2022-03-28 | GSE186758 | GEO

Polycomb associates genome-wide with a specific RNA polymerase II variant, and regulates metabolic genes in ES cells (ChIP-Seq)

Project description:Polycomb repressor complexes (PRCs) are important chromatin modifiers fundamentally implicated in pluripotency and cancer. Polycomb silencing in embryonic stem cells (ESCs) can be accompanied by active chromatin and primed RNA polymerase II (RNAPII), but the relationship between PRCs and RNAPII remains unclear at the genome-wide level. We mapped PRC repression markers and four RNAPII states in ESCs using ChIP-seq, and found that PRC-targets exhibit a range of RNAPII variants. Firstly, developmental PRC-targets are bound by unproductive RNAPII (S5p+S7p- S2p-) genome-wide. Sequential ChIP, Ring1B-depletion and genome-wide correlations show that PRCs and RNAPII-S5p physically bind to the same chromatin and functionally synergize. Secondly, we identify a cohort of genes marked by PRC and elongating RNAPII (S5p+S7p+S2p+); they produce mRNA and protein, and their expression increases upon PRC1 knockdown. We show that this novel group of PRC-targets switch between active and PRC-repressed states within the ESC population, and that many have roles in metabolism. **Correction (Mar 14, 2012): Due to curation error, runs for SRX112177 and SRX112179 switched, specifically, Run SRR391034.1 was removed from experiment SRX112177 (GSM850468) and added to experiment SRX112179 (GSM850470) as SRR391034.3 Run SRR391040.1 was removed from experiment SRX112179 (GSM850470) and added to experiment SRX112177 (GSM850468) as SRR391040.3 Examination of 4 different RNAPII modifications (S5p, S7p, 8WG16, S2p), and the histone modifications H2Aub1 and H3K36me3 in mouse ES cells

2012-02-01 | E-GEOD-34518 | biostudies-arrayexpress

Polycomb associates genome-wide with a specific RNA polymerase II variant, and regulates metabolic genes in ES cells (ChIP-Seq)

2012-02-01 | GSE34518 | GEO

Determinants of H3K4me pattern establishment

Project description:A hallmark of genes transcribed by RNA polymerase II (RNApII) is a "gradient" of histone H3 lysine 4 (H3K4) methylation. Various factors differentially bind to H3K4me3 near promoters, H3K4me2 just downstream, and H3K4me1 further downstream to modulate gene expression. Set1/COMPASS, the single S. cerevisiae H3K4 methyltransferase, binds transcribing RNApII, but COMPASS may also be allosterically regulated by specific subunits and histone H2B ubiquitylation. To ask whether differential H3K4 methylation is determined by regulated activity at specific gene locations or by the amount of time COMPASS spends near the nucleosome, ChIP-Seq analyses was performed in cells with altered transcription elongation rates or with Set1 fused to RNApII. Our results support a simple model where higher H3K4 methylations result from both increased duration and frequency of COMPASS proximity to the nucleosome.

2017-11-12 | GSE95356 | GEO

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