Structural and functional divergence of cancer hotspot mutations in CREBBP
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE337323 | GEO | 2026/09/06
REPOSITORIES: GEO
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Project description:The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and has been studied using gene knock-out (KO) in murine and human cells. However, the majority of CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell-lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor, thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of transcription factor, or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear transcription factor abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. We therefore provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects.
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Project description:Truncating and missense mutations of the CREBBP gene are highly prevalent in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancies. These mutations are acquired early during tumor evolution and lead to either complete protein loss or single amino acid substitutions in the acetyltransferase (KAT) domain. As a consequence, CREBBP is impaired in its ability to acetylate enhancer histones as well as non-histone proteins implicated in the germinal center (GC) reaction, the structure from which these tumors originate. However, whether truncating and missense mutations of the KAT domain are functionally equivalent remains unexplored. Using a conditional GC-specific knock-in mouse model for the highly frequent Crebbp-R1446H amino-acid change (CrebbpRH), here we show that, compared to complete Crebbp loss, missense mutants impose distinct quantitative and qualitative effects on the GC response. CrebbpRH mutation controls unique transcriptional programs leading to the pre-neoplastic expansion of GCs with abnormal architecture, increased percentage of Tfh cells, and a skewed immune response toward memory B cell differentiation. Expression of CrebbpRH, but not Crebbp loss, was by itself sufficient to initiate malignant transformation in vivo, indicating a stronger tumor-promoting activity. Our findings, together with the differential distribution of missense and truncating mutations in FL and DLBCL, have implications for the mechanisms underlying lymphomagenesis and their therapeutic targeting.
2026-06-25 | GSE292384 | GEO
Project description:Rubinstein-Taybi syndrome (RTS) is a rare and severe genetic developmental disorder characterized by multiple congenital anomalies and intellectual disability. CREBBP and EP300, the two genes known to cause RTS encode transcriptional coactivators with a catalytic lysine acetyltransferase (KAT) activity. Loss of CBP or p300 function results in a deficit in protein acetylation, in particular at histones. In RTS, nothing is known on the consequences of the loss of histone acetylation on the transcriptomic profiles during neuronal differentiation. To address this question, we differentiated induced pluripotent stem cells from RTS patients carrying a recurrent CREBBP mutation that inactivates the KAT domain into cortical and pyramidal neurons. By comparing their acetylome and their transcriptome at different neuronal differentiation timepoints, we identified 25 specific acetylated histone residues altered in RTS. We also identified the transition between neural progenitors and immature neurons as a critical step of the differentiation process, with a delayed neuronal maturation in RTS.
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Project description:The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
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Project description:The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
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Project description:The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
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Project description:The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
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Project description:The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
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Project description:The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
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