Polymerization of ZBTB transcription factors regulates chromatin occupancy.

BCL6, an oncogenic transcription factor (TF), forms polymers in the presence of a small-molecule molecular glue that stabilizes a complementary interface between homodimers of BCL6's broad-complex, tramtrack, and bric-à-brac (BTB) domain. The BTB domains of other proteins, including a large class of TFs, have similar architectures and symmetries, raising the possibility that additional BTB proteins self-assemble into higher-order structures. Here, we surveyed 189 human BTB proteins with a cellular fluorescent reporter assay and identified 18 ZBTB TFs that show evidence of polymerization. Through biochemical and cryoelectron microscopy (cryo-EM) studies, we demonstrate that these ZBTB TFs polymerize into filaments. We found that BTB-domain-mediated polymerization of ZBTB TFs enhances chromatin occupancy within regions containing homotypic clusters of TF binding sites, leading to repression of target genes. Our results reveal a role of higher-order structures in regulating ZBTB TFs and suggest an underappreciated role for TF polymerization in modulating gene expression.

UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.

Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.

Template-assisted covalent modification underlies activity of covalent molecular glues.

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed 'template-assisted covalent modification'. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes the formation of BRD4-degrader-DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK-BRD4BD2 interaction through trans-labeling of GAK. Together, our work establishes 'template-assisted covalent modification' as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.

BET-bromodomain and EZH2 inhibitor-treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes.

Despite advances in the field, chronic graft-versus-host-disease (cGVHD) remains a leading cause of morbidity and mortality following allogenic hematopoietic stem cell transplant. Because treatment options remain limited, we tested efficacy of anticancer, chromatin-modifying enzyme inhibitors in a clinically relevant murine model of cGVHD with bronchiolitis obliterans (BO). We observed that the novel enhancer of zeste homolog 2 (EZH2) inhibitor JQ5 and the BET-bromodomain inhibitor JQ1 each improved pulmonary function; impaired the germinal center (GC) reaction, a prerequisite in cGVHD/BO pathogenesis; and JQ5 reduced EZH2-mediated H3K27me3 in donor T cells. Using conditional EZH2 knockout donor cells, we demonstrated that EZH2 is obligatory for the initiation of cGVHD/BO. In a sclerodermatous cGVHD model, JQ5 reduced the severity of cutaneous lesions. To determine how the 2 drugs could lead to the same physiological improvements while targeting unique epigenetic processes, we analyzed the transcriptomes of splenic GCB cells (GCBs) from transplanted mice treated with either drug. Multiple inflammatory and signaling pathways enriched in cGVHD/BO GCBs were reduced by each drug. GCBs from JQ5- but not JQ1-treated mice were enriched for proproliferative pathways also seen in GCBs from bone marrow-only transplanted mice, likely reflecting their underlying biology in the unperturbed state. In conjunction with in vivo data, these insights led us to conclude that epigenetic targeting of the GC is a viable clinical approach for the treatment of cGVHD, and that the EZH2 inhibitor JQ5 and the BET-bromodomain inhibitor JQ1 demonstrated clinical potential for EZH2i and BETi in patients with cGVHD/BO.

Titanium dioxide fiber saturable absorber for Q-switched fiber laser generation in the 1-micrometer region: publisher's note.

This publisher's note serves to correct an error in Appl. Opt. 58, 3495 (2019)APOPAI0003-693510.1364/AO.58.003495.

High-efficiency picosecond mode-locked laser using a thulium-doped nanoengineered yttrium-alumina-silica fiber as the gain medium.

We report the theoretical and experimental investigation of a self-starting mode-locked fiber laser with a nanoengineered Tm3+-doped yttrium-alumina-silica (YAS) fiber as the gain medium. The YAS fiber exhibits a higher capability of Tm3+ cluster elimination than commercial silica fibers. The Tm3+ fluorescence properties and YAS dispersion are well characterized. As a result, an efficient picosecond mode-locked fiber laser is demonstrated with a slope efficiency of 14.14% and maximum pulse energy of 1.27 nJ. To the best of our knowledge, this is the first mode-locked fiber laser based on a Tm3+-doped YAS fiber. The experimental observation is also supported by the numerical analysis.

Titanium dioxide fiber saturable absorber for Q-switched fiber laser generation in the 1-micrometer region.

A passively Q-switched ytterbium-doped fiber laser (YDFL) operating at 1062 nm was demonstrated by using a segment of 20 cm titanium dioxide-doped fiber saturable absorber (TiO2DF SA). The Q-switched YDFL emerged stably with tunable repetition rates ranging from 32 kHz to 53 kHz as the pump power rose from 109 mW to 233 mW. Within this range of pump power, a maximum output power of 10.1 mW, maximum peak power of 75 mW, and maximum pulse energy of 191 nJ were obtained. The narrowest pulse width of 2.55 µs was attained at the maximum pump power of 233 mW, while the signal-to-noise ratio of the fundamental frequency was 47 dB. This demonstration reveals that the proposed TiO2DF SA is feasible for constructing a flexible and reliably stable Q-switched pulsed fiber laser in the 1-micrometer region.

Noise in the intensive care unit and its influence on sleep quality: a multicenter observational study in Dutch intensive care units.

BACKGROUND: High noise levels in the intensive care unit (ICU) are a well-known problem. Little is known about the effect of noise on sleep quality in ICU patients. The study aim is to determine the effect of noise on subjective sleep quality. METHODS: This was a multicenter observational study in six Dutch ICUs. Noise recording equipment was installed in 2-4 rooms per ICU. Adult patients were eligible for the study 48 h after ICU admission and were followed up to maximum of five nights in the ICU. Exclusion criteria were presence of delirium and/or inability to be assessed for sleep quality. Sleep was evaluated using the Richards Campbell Sleep Questionnaire (range 0-100 mm). Noise recordings were used for analysis of various auditory parameters, including the number and duration of restorative periods. Hierarchical mixed model regression analysis was used to determine associations between noise and sleep. RESULTS: In total, 64 patients (68% male), mean age 63.9 (± 11.7) years and mean Acute Physiology And Chronic Health Evaluation (APACHE) II score 21.1 (± 7.1) were included. Average sleep quality score was 56 ± 24 mm. The mean of the 24-h average sound pressure levels (LAeq, 24h) was 54.0 dBA (± 2.4). Mixed-effects regression analyses showed that background noise (ß = - 0.51, p < 0.05) had a negative impact on sleep quality, whereas number of restorative periods (ß = 0.53, p < 0.01) and female sex (ß = 1.25, p < 0.01) were weakly but significantly correlated with sleep. CONCLUSIONS: Noise levels are negatively associated and restorative periods and female gender are positively associated with subjective sleep quality in ICU patients. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01826799 . Registered on 9 April 2013.

Evaluation of an activity monitor for use in pregnancy to help reduce excessive gestational weight gain.

BACKGROUND: Excessive weight gain during pregnancy increases the risk for negative effects on mother and child during pregnancy, delivery, and also postnatally. Excessive weight gain can be partially compensated by being sufficiently physically active, which can be measured using activity trackers. Modern activity trackers often use accelerometer data as well as heart rate data to estimate energy expenditure. Because pregnancy affects the metabolism and cardiac output, it is not evident that activity trackers that are calibrated to the general population can be reliably used during pregnancy. We evaluated whether an activity monitor designed for the general population is sufficiently accurate for estimating energy expenditure in pregnant women. METHODS: Forty pregnant women (age: 30.8 ± 4.7 years, BMI: 25.0 ± 4.0) from all three trimesters performed a 1-h protocol including paced and self-paced exercise activities as well as household activities. We tracked reference energy expenditure using indirect calorimetry and used equivalence testing to determine whether the estimated energy expenditure from the activity monitor was within the limits of equivalence. RESULTS: Overall we found an averaged underestimation of 10 kcal (estimated energy expenditure was 97% of the reference measurement). The 90% CI for the cumulative total energy expenditure was 94-100%. The activities of self-paced cycling, household activities, stair-walking, and yoga had one of their equivalence boundaries outside a 80-125% range of equivalence; for exercise on a cross-trainer, for self-paced and fixed-pace walking, fixed-paced cycling, and resting, the estimations were within the limits of equivalence. CONCLUSIONS: We conclude that the activity monitor is sufficiently accurate for every-day use during pregnancy. The observed deviations can be accounted for and are acceptable from a statistical and an applied perspective because the positive and negative deviations that we observed cancel out to an accurate average energy expenditure over a day, and estimations during exercise are sufficiently accurate to enable coaching on physical activity. The positive and negative deviations themselves were relatively small. Therefore, the activity monitor can be used to help in preventing excessive weight gain during pregnancy by accurately tracking physical activity.

Women generating narratives after an unwanted prenatal diagnosis result: randomized controlled trial.

We have defined a psychological intervention based on cognitive narrative therapy and the Ottawa decision framework to reduce adjustment problems following a termination of pregnancy (TOP) after a positive prenatal diagnosis (PND). The intervention is composed of four sessions: decision, subjectivation, metaphorization, and projecting. This study aims to assess the effectiveness of a cognitive narrative intervention to prevent depression and anxiety symptoms after TOP. The intervention was accepted by 24 participants. The outcome is compared with a control group of 67 women who also terminated a pregnancy after PND. Participants were from several Portuguese institutions; 64.4% had a genetic and 35.6% had ultrasound diagnosis; the mean age was 30.0 years and the mean gestational age was 19 weeks. There are two evaluations: a baseline at the 15th day and a sixth month follow-up after TOP, using Beck Depression Inventory, Zung Anxiety Scale, Perinatal Grief Scale, and an instrument capturing participant satisfaction. Six months after TOP, there is a lower mean of anxiety and depression (p < 0.05), between groups, with effect sizes on the follow-up of 0.54 for depression, 0.41 for anxiety, and 0.23 for perinatal grief. This intervention has very positive effects on women mental health, and we emphasize the importance of the meaning-making process in the context of terminating a wanted pregnancy.

Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation.

OBJECTIVE: To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD). DESIGN: Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants. RESULTS: IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS. CONCLUSIONS: In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.

Mode-locked thulium bismuth codoped fiber laser using graphene saturable absorber in ring cavity: reply.

Jung and Lee have made comments [Appl. Opt.53, 553-554 (2014)] on "Mode-locked thulium bismuth codoped fiber laser using Graphene saturable absorber in ring cavity" [Appl. Opt.52, 1226-1229 (2013)]. The answer for the comment is provided in this report.

Mode-locked thulium-bismuth codoped fiber laser using graphene saturable absorber in ring cavity.

We demonstrate mode locking of a thulium-bismuth codoped fiber laser (TBFL) operating at 1901.6 nm, using a graphene-based saturable absorber (SA). In this work, a single layer graphene is mechanically exfoliated using the scotch tape method and directly transferred onto the surface of a fiber pigtail to fabricate the SA. The obtained Raman spectrum characteristic indicates that the graphene on the core surface has a single layer. At 1552 nm pump power of 869 mW, the mode-locked TBFL self starts to generate an optical pulse train with a repetition rate of 16.7 MHz and pulse width of 0.37 ps. This is a simple, low-cost, stable, and convenient laser oscillator for applications where eye-safe and low-photon-energy light sources are required, such as sensing and biomedical diagnostics.

Five-Year Follow-up of Third-Generation Percutaneous Chevron and Akin Osteotomies (PECA) for Hallux Valgus.

BACKGROUND: Recent large studies of third-generation minimally invasive hallux valgus surgery (MIS) have demonstrated significant improvement in clinical and radiologic outcomes. It remains unknown whether these clinical and radiologic outcomes are maintained in the medium to long term. The aim of this study was to investigate the minimum 5-year clinical and radiologic outcomes following third-generation MIS hallux valgus surgery in the hands of a high-volume MIS surgeon. METHODS: A retrospective observational single highly experienced MIS surgeon case series of consecutive patients undergoing primary isolated third-generation percutaneous chevron and Akin osteotomies (PECA) for hallux valgus with a minimum 60-month clinical and radiographic follow-up. Primary outcome was radiographic assessment of the hallux valgus angle (HVA) and intermetatarsal angle (IMA) preoperatively, 6 months, and ≥60 months following PECA. Secondary outcomes included the Manchester-Oxford Foot Questionnaire, patient satisfaction, EuroQol-5D visual analog scale and the visual analog scale for pain. RESULTS: Between 2012 and 2014, 126 consecutive feet underwent isolated third-generation PECA, with complete data available for 78 (61.9%) feet. The median follow-up was 65.0 (IQR 64-69; range 60-88) months. There was a significant improvement in radiographic deformity correction; the median IMA improved from 12.0 degrees (interquartile range [IQR]: 10.8-14.2) to 6.0 degrees (IQR: 4.2-7.3) (P < .001), and the median HVA improved from 27.2 degrees (IQR: 20.6-34.4) to 7.2 degrees (IQR: 3.4-11.6). Median MOXFQ Index score at ≥60-month follow-up was 2.3 (IQR: 0.0-7.8). The radiographic recurrence rate (defined as HVA >15 degrees) was 7.7% at final follow-up. The complication rate was 4.8%. CONCLUSION: Radiologic deformity correction for the 78 feet we were able to follow that had third-generation PECA performed by a single highly experienced MIS surgeon was found to be maintained at a mean follow-up of average 66.8 months, with a radiographic recurrence rate of 7.7%. Clinical PROMs and patient satisfaction levels were high and comparable to other third-generation studies with shorter duration of follow-up. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

The human E3 ligase RNF185 is a regulator of the SARS-CoV-2 envelope protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks multiple human proteins during infection and viral replication. To examine whether any viral proteins employ human E3 ubiquitin ligases, we evaluated the stability of SARS-CoV-2 proteins with inhibition of the ubiquitin proteasome pathway. Using genetic screens to dissect the molecular machinery involved in the degradation of candidate viral proteins, we identified human E3 ligase RNF185 as a regulator of protein stability for the SARS-CoV-2 envelope protein. We found that RNF185 and the SARS-CoV-2 envelope co-localize to the endoplasmic reticulum (ER). Finally, we demonstrate that the depletion of RNF185 significantly increases SARS-CoV-2 viral titer in a cellular model. Modulation of this interaction could provide opportunities for novel antiviral therapies.

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.

Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells.

OBJECTIVES: Recent evidence suggests a role for increased colonic permeability and mucosal mast cell (MC) mediators on symptoms related to the irritable bowel syndrome (IBS). Whether allergic factors (AFs) are involved in the pathophysiology of IBS is unclear. We addressed the question of the possible influence of an allergic background on IBS symptoms. METHODS: We assessed paracellular permeability, mucosal MCs counts, and spontaneous release of tryptase of colonic biopsy specimens in 34 IBS patients and 15 healthy subjects. The severity of IBS was assessed through self-reported questionnaires. All individuals were tested for the presence of AF, including self-perception of adverse reaction to food, personal and familial history of atopic disease, elevated total or specific immunoglobulin E against food/inhalant antigens, blood eosinophilia, and skin tests. RESULTS: IBS patients had significant enhanced colonic permeability, higher number of MCs, and spontaneous release of tryptase than healthy subjects. The severity of IBS was significantly correlated with colonic permeability (r=0.48, P=0.004), MCs counts (r=0.36, P=0.03), and tryptase (r=0.48, P=0.01). In 13 IBS patients (38.2%) having at least three AFs, symptoms scores, colonic permeability, MCs counts, and tryptase release by colonic biopsies were significantly higher than in those with less than three AFs. IBS patients with at least three AFs were more prone to diarrhea or alternating symptoms. None AF was found to be predictive of IBS severity. CONCLUSIONS: In IBS patients, the presence of an allergic background correlates with a more severe disease and diarrhea predominance, possibly by enhancing mucosal MC activation and paracellular permeability.

Unravelling direct and indirect contact patterns between duck farms in France and their association with the 2016-2017 epidemic of Highly Pathogenic Avian Influenza (H5N8).

Live animal movements generate direct contacts (via the exchange of live animals) and indirect contacts (via the transit of transport vehicles) between farms, which can contribute to the spread of pathogens. However, most analyses focus solely on direct contacts and can therefore underestimate the contribution of live animal movements in the spread of infectious diseases. Here, we used French live duck movement data (2016-2018) from one of the largest transport companies to compare direct and indirect contact patterns between duck farms and evaluate how these patterns were associated with the French 2016-2017 epidemic of highly pathogenic avian influenza H5N8. A total number of 614 farms were included in the study, and two directed networks were generated: the animal introduction network (exchange of live ducks) and the transit network (transit of transport vehicles). Following descriptive analyses, these two networks were scrutinized in relation to farm infection status during the epidemic. Results showed that farms were substantially more connected in the transit network than in the animal introduction network and that the transit of transport vehicles generated more opportunities for transmission than the exchange of live animals. We also showed that animal introduction and transit networks' statistics decreased substantially during the epidemic (January-March 2017) compared to non-epidemic periods (January-March 2016 and January-March 2018). We estimated a probability of 33.3 % that a farm exposed to the infection through either of the two live duck movement networks (i.e. that was in direct or indirect contact with a farm that was reported as infected in the following seven days) becomes infected within seven days after the contact. However, we also demonstrated that the level of exposure of farms by these two contact patterns was low, leading only to a handful of transmission events through these routes. As a consequence, we showed that live animal movement patterns are efficient transmission routes for HPAI but have been efficiently reduced to limit the spread during the French 2020-2021 epidemic. These results underpin the relevance of studying indirect contacts resulting from the movement of animals to understand their transmission potential and the importance of accounting for both routes when designing disease control strategies.

Valgus Second Toe Deformity Treated With a Percutaneous Extracapsular Closing-Wedge Osteotomy of the Proximal Phalanx.

BACKGROUND: Coronal and sagittal plane deformities of the lesser toes are common yet challenging to treat. Traditional open releases and translational Weil osteotomies can be unpredictable and lead to postoperative stiffness. We present the results of a percutaneous closing wedge extracapsular osteotomy of the proximal phalanx to treat valgus deformity of the second toe. METHODS: Thirty-one patients underwent 40 percutaneous osteotomies at a median age of 58.6±9.4 years. Using a small dorsomedial incision, a percutaneous proximal metaphyseal medial closing-wedge extracapsular osteotomy of the second toe is performed, leaving the dorsolateral cortex intact. An irrigated low-speed, high-torque 2- × 8-mm burr is used under image guidance. The osteotomy is then closed to correct deformity and taped for 2 weeks. Patient-reported outcomes and weightbearing radiographs were obtained. RESULTS: Questionnaire data was available for 89.7% (n=35) of cases. Most cases (91.4%) were either satisfied or extremely satisfied with the procedure. Radiographs were available for 90.0% of osteotomies, with a median length from surgery to radiographic follow-up of 1.6 years (range 0.5-6.3; SD ±1.5). Median second-toe valgus angle (STVA) decreased from 16.2±10.7 degrees to 5.0±7.0 degrees (P < .001) at final follow-up. All osteotomies united with no delayed union. There were no wound complications or infections. We found 2 cases of radiographic recurrence. CONCLUSION: Percutaneous proximal phalanx base metaphyseal closing wedge extracapsular osteotomies of lesser toes to correct coronal plane deformity is useful adjunct to first-ray corrective surgery and is associated with high levels of patient satisfaction. LEVEL OF EVIDENCE: Level IV, retrospective case series.

EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma.

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2ß, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed "JQAD1" that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells. SIGNIFICANCE: EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2ß. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner. This article is highlighted in the In This Issue feature, p. 587.