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Results for “p300/CBP”

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5 recordsLinked to original sources
PubMed2025

p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.

The t(11;22) translocation encodes the EWS::FLI1 fusion oncoprotein which is the primary driver of Ewing sarcoma. EWS::FLI1 creates unique, de novo pathogenic enhancers that drive gene expression and are a central mechanism of oncogenesis. Which chromatin regulatory proteins are critical to this mechanism is understudied. Here, we perform a comparative analysis of the function of the chromatin complexes MLL3/4 and p300/CBP in EWS::FLI1-mediated gene regulation. Using EWS::FLI1 degradation models, we define a subset of EWS::FLI1-sensitive enhancers whose activity correlates with p300/CBP function. We perturb both chromatin complexes to establish that in contrast to MLL3/4, p300/CBP is a critical regulator of EWS::FLI1-driven enhancer activity and downstream gene expression. We also show that p300/CBP small-molecule inhibition decelerates tumor growth in vivo. Our work highlights the context-dependent nature of chromatin protein activity at oncogenic enhancers and reveals p300/CBP as an important regulator of Ewing sarcoma.

Sarcoma, Ewing↗
PubMed2025

Dual EZH1/2 inhibition enhances DNMT inhibitor efficacy in colon cancer through targeting H3K27me1.

Our recent work showed that low-dose DNMT inhibitor (DNMTi) treatment sensitizes colon cancer cells to EZH2 inhibitors (EZH2i), synergistically upregulating tumor suppressor genes (TSGs) and transposable elements through activation of the calcium-calcineurin-NFAT signaling pathway. A key observation was that EZH2i displayed variable sensitivities in combination therapy, which could not be explained solely by loss of lysine 27 trimethylation on histone H3 (H3K27me3), the most commonly studied EZH2 product. This led us to perform a comprehensive pharmacologic screen of Polycomb Repressive Complex 2 (PRC2) antagonists. Here, we show that compounds targeting both EZH2 and its interchangeable catalytic subunit, EZH1, achieved superior TSG re-expression when combined with DNMTi. Integrative proteomic and epigenomic analyses revealed that EZH1/2 inhibitors reduce all three H3K27 methylation states, whereas EZH2-selective inhibitors preserve EZH1-dependent H3K27me1 at deeply Polycomb-repressed genomic regions. Notably, H3K27me1 loss coincided with deposition of p300/CBP-dependent lysine 27 acetylation on histone H3 (H3K27ac), which proved essential for TSG re-expression. Paradoxically, blocking p300/CBP activity further enhanced the growth-inhibitory effects of combined DNMT and EZH1/2 inhibition. Mechanistically, we show that EZH1/2 inhibition redistributes p300/CBP activity, reducing H3K27ac from oncogenic loci and redirecting it to bivalent regions that enable TSG re-expression. Collectively, these findings reveal a coordinated role for EZH1-dependent H3K27me1 and DNA methylation in sustaining oncogenic transcriptional programs and provide strong rationale for advancing dual EZH1/2 inhibitors for combination epigenetic cancer therapy.

DNA methylation↗
PubMed2026

Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling.

Transcriptional remodelling during fasting ensures metabolic adaptation and provides health benefits across species. Although several regulators of fasting-induced transcription and chromatin are known, how nutrient levels directly influence RNA polymerase II (RNAPII) and epigenetic writers remains unclear. Here we show that lipid kinase class 3 phosphatidylinositol 3-kinase (PI3K-3), a master regulator of autophagy, also functions on chromatin as a co-activator of epigenetic writers to promote RNAPII transcription. PI3K-3 overlaps with transcriptionally engaged RNAPII phosphorylated at Ser5 and with Setd1a/COMPASS, the complex that deposits the activating H3K4me3 mark. Nuclear PI3K-3 interacts with RNAPII and Setd1a/COMPASS and promotes their chromatin binding. PI3K-3 loss reduces RNAPII-S5p and H3K4me3 at selected genes, whereas PI3K-3 overexpression co-activates p300/CBP and chromatin-targeted PI3K-3 increases H3K4me3. During starvation, PI3K-3 induces autophagy genes and drives fasted liver towards ketogenesis and lipid degradation. These findings link nutrient stress to chromatin-mediated transcriptional activation.

Chromatin Assembly and Disassembly↗
PubMed2026

MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.

Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with the significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for the nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the coactivators P300/CBP. All these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter cross talk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.

Promoter Regions, Genetic↗
PubMed2026

Biomolecular Condensates Integrate Transcriptional and Epigenetic Responses to Hypoxia.

Hypoxia is a defining feature of physiological stress and the core of solid tumors, where aberrant vascularization limits oxygen delivery; cells respond through mechanisms that extend beyond the canonical stabilization of hypoxia-inducible factors (HIFs). Recent studies suggest that hypoxia can promote the formation of specific biomolecular conden-sates, membraneless compartments generated through liquid-liquid phase separation in which regulatory proteins and RNAs become locally enriched at genomic regions, while chromatin mainly serves as an organizational scaffold. Transcription factors, the coacti-vators p300/CBP, Mediator, and BRD4, chromatin-modifying enzymes, and architectural RNAs such as NEAT1 and MALAT1 partition into these compartments, and their con-densation can help reorganize local chromatin structure and enhancer-promoter interac-tions. Because molecular oxygen is a shared co-substrate for the Jumonji-C histone demethylases and the ten-eleven translocation (TET) DNA dioxygenases, hypoxia reshapes histone methylation and DNA methylation in parallel, and readers that bridge these marks, including UHRF1, may participate in condensate-associated chromatin regulation. Hypoxia-driven condensation of ZHX2 rewires enhancer-promoter contacts and higher-order genome architecture, influencing cell identity, stemness, and metastatic potential, and Polycomb condensates represent another candidate epigenetic compartment that may be influenced by hypoxic signaling. These processes may be particularly important in cancer, where chronic hypoxia provides a sustained stimulus for condensate formation and epigenetic remodeling. Together, these findings support a model in which phase separation and epigenetic reprogramming are not separate layers but one integrated response to low oxygen, offering opportunities to target maladaptive condensates in disease.

Epigenesis, Genetic↗