CDK9-mediated phosphorylation controls the interaction of TIP60 with the transcriptional machinery.

The acetyltransferase TIP60 is regulated by phosphorylation, and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53-mediated induction of the BCL-2 protein PUMA. TIP60 phosphorylation by GSK-3 requires a priming phosphorylation on S90, and here, we identify CDK9 as a TIP60S90 kinase. We demonstrate that a phosphorylation-deficient mutant, TIP60S90A, exhibits reduced interaction with chromatin, histone 3 and RNA Pol II, while its association with the TIP60 complex subunit EPC1 is not affected. Consistently, we find a diminished association of TIP60S90A with the MYC gene. We show that cells expressing TIP60S90A, but also TIP60S86A, which retains S90 phosphorylation, exhibit reduced histone 4 acetylation and proliferation. Thus, our data indicate that, during transcription, phosphorylation of TIP60 at two sites has different regulatory effects on TIP60, whereby S90 phosphorylation controls association with the transcription machinery, and S86 phosphorylation is regulating TIP60 HAT activity.

Emicizumab is well tolerated and effective in people with congenital hemophilia A regardless of age, severity of disease, or inhibitor status: a scoping review.

Background: With the treatment landscape continually evolving, it is vital that the hemophilia community have an overview of all published data for approved therapies, such as emicizumab, to support shared decision making. Objectives: To bring together the clinical and real-world data for emicizumab use in people with congenital hemophilia A, regardless of age, disease severity, or factor VIII inhibitor status. Key focus areas were safety, efficacy, and quality of life (QoL). Methods: This scoping review used citation databases (PubMed, Embase, and the Cochrane Library) and manual searches of abstract books. Publications reporting original data for emicizumab in people with hemophilia A, published in English after December 2014, and reporting select endpoints were included. This narrative synthesis focused on zero bleeds, treated annualized bleeding rate (ABR), adverse events, and QoL measures. Results: Overall, 97 publications were included (cut-off: August 9, 2022). Treated ABR remained low (calculated mean and median treated ABRs ranged between 0.7-1.3 and 0.0-1.4, respectively), and the median percentage of people with zero treated bleeds was 66.7%. The proportion of people experiencing treatment-related adverse events ranged from 0.0% to 60.0%; most were injection-site reactions. Across 37 publications reporting on safety and enrolling >2300 individuals, 11 thrombotic events and 4 thrombotic microangiopathies were reported. Data from well-established tools show QoL benefits with emicizumab. Conclusion: This scoping review consolidates the global published experience for emicizumab in people with hemophilia A and supports the fact that emicizumab has an acceptable safety profile, is effective and efficacious in bleed prevention, and is associated with improvements in QoL.

Aggressive PDACs Show Hypomethylation of Repetitive Elements and the Execution of an Intrinsic IFN Program Linked to a Ductal Cell of Origin.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylationlow tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylationlow/IFNsignhigh and Methylationhigh/IFNsignlow PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived Kras G12D/Trp53 -/- mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylationlow/IFNsignhigh subtype potentially targetable by agents blocking intrinsic IFN signaling. SIGNIFICANCE: The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity.This article is highlighted in the In This Issue feature, p. 521.