Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation.

Chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. This activity is restricted to variant PRC1 complexes, and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for normal polycomb domain formation and mouse development. These observations provide a surprising PRC1-dependent logic for PRC2 occupancy at target sites in vivo.

Screening for functional regulatory variants in open chromatin using GenIE-ATAC.

Understanding the effects of genetic variation in gene regulatory elements is crucial to interpreting genome function. This is particularly pertinent for the hundreds of thousands of disease-associated variants identified by GWAS, which frequently sit within gene regulatory elements but whose functional effects are often unknown. Current methods are limited in their scalability and ability to assay regulatory variants in their endogenous context, independently of other tightly linked variants. Here, we present a new medium-throughput screening system: genome engineering based interrogation of enhancers assay for transposase accessible chromatin (GenIE-ATAC), that measures the effect of individual variants on chromatin accessibility in their endogenous genomic and chromatin context. We employ this assay to screen for the effects of regulatory variants in human induced pluripotent stem cells, validating a subset of causal variants, and extend our software package (rgenie) to analyse these new data. We demonstrate that this methodology can be used to understand the impact of defined deletions and point mutations within transcription factor binding sites. We thus establish GenIE-ATAC as a method to screen for the effect of gene regulatory element variation, allowing identification and prioritisation of causal variants from GWAS for functional follow-up and understanding the mechanisms of regulatory element function.

Do Early Relapses Predict the Risk of Long-Term Relapsing Disease in an Adult and Paediatric Cohort with MOGAD?

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer-term relapse risk is unknown. Here, we investigate whether early relapses increase longer-term relapse risk in patients with MOGAD. METHODS: A retrospective analysis of 289 adult- and pediatric-onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. "Early relapses" were defined as attacks within the first 12 months from onset, with "very early relapses" defined within 30 to 90 days from onset and "delayed early relapses" defined within 90 to 365 days. "Long-term relapses" were defined as relapses beyond 12 months. Cox regression modeling and Kaplan-Meier survival analysis were used to estimate the long-term relapse risk and rate. RESULTS: Sixty-seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long-term relapses if any "early relapses" were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long-term relapses (HR = 2.64, p = 0.026). INTERPRETATION: The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long-term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric-onset disease. ANN NEUROL 2023;94:508-517.

Tracing womyn-born-womyn & trans-exclusion: Into the Michigan Womyn's Music Festival archive.

Few events evoke a divisive response amongst lesbians like the mentioning of the Michigan Womyn's Music Festival. Autoethnographies, interviews, podcasts, and books - just to name a few - continue to be crafted even after the forty-year festival's end. Unlike previous publications, this article approaches the festival using archival materials housed at Michigan State University donated by producer, Lisa Vogel, to unpack the signaling rhetoric of womyn-born-womyn (WBW). I center the experience Nancy Burkholder, a transsexual woman expelled from the festival, to navigate, as Nancy tried to navigate, the WBW "policy." I then take readers on a journey into the archive and articulate my research through calculated steps of tracing language through years of the festival. This article demonstrates how documents, created by festival producers, incited confusion for Nancy Burkholder during the festival and how these same documents now sustain an archival ambiguity.

Mucosal Atrophy Predicts Poorer Outcomes in Pediatric Ulcerative Colitis-A National Inception Cohort Study.

BACKGROUND: Outcomes in pediatric ulcerative colitis (UC) are heterogeneous and predictors of disease course eagerly sought. Mucosal atrophy (MA) is characterized by histological abnormalities of colonic intestinal glands. OBJECTIVE: To determine the prevalence of MA in a national inception cohort of pediatric UC and its impact on outcomes. METHODS: Irish children < 16 years old with UC are diagnosed at a single referral center. At diagnosis, patients underwent phenotyping by Paris classification and activity assessment by Pediatric Ulcerative Colitis Activity Index. Biopsies from all colonic segments were evaluated for MA. Patients were followed prospectively. The primary outcome was corticosteroid-free remission at 1 year. Secondary outcomes included relapse, treatment escalation, and colectomy by 2 years. RESULTS: Of 251 pediatric patients with UC (mean age 11.8 years, 55% male), 38 (15%) had MA on diagnostic biopsy. Baseline characteristics were similar between groups with/without MA and there was no difference in steroid-free remission or rates of moderate-severe UC at 1 year. Patients with MA had higher use of steroids (29% vs 15%, P = 0.04) and immunomodulators (40% vs 21%, P = 0.04) at 6 months, higher biologic use at 1 year (34% vs 16%, P = 0.03), earlier first relapse (mean ± SD 29.4 ± 26.1 vs 46.7 ± 43.4 weeks after diagnosis, P = 0.02), and higher colectomy rates by 2 years (21% vs 8%, P = 0.01). CONCLUSIONS: Children with MA at diagnosis had higher colectomy rates despite earlier treatment escalation and similar baseline severity scores. We identify MA as a promising new prognostic marker in children with newly diagnosed UC.

Vaccination coverage in rural Burkina Faso under the effects of COVID-19: evidence from a panel study in eight districts.

BACKGROUND: Improving infant immunization completion and promoting equitable vaccination coverage are crucial to reducing global under-5 childhood mortality. Although there have been hypotheses that the impact of the COVID-19 pandemic would decrease the delivery of health services and immunization campaigns in low- and middle-income countries, the available evidence is still inconclusive. We conducted a study in rural Burkina Faso to assess changes in vaccination coverage during the pandemic. A secondary objective was to examine long-term trends in vaccination coverage throughout 2010-2021. METHODS: Using a quasi-experimental approach, we conducted three rounds of surveys (2019, 2020, 2021) in rural Burkina Faso that we pooled with two previous rounds of demographic and household surveys (2010, 2015) to assess trends in vaccination coverage. The study population comprised infants aged 0-13 months from a sample of 325 households randomly selected in eight districts (n = 736). We assessed vaccination coverage by directly observing the infants' vaccination booklet. Effects of the pandemic on infant vaccination completion were analyzed using multi-level logistic regression models with random intercepts at the household and district levels. RESULTS: A total of 736 child-year observations were included in the analysis. The proportion of children with age-appropriate complete vaccination was 69.76% in 2010, 55.38% in 2015, 50.47% in 2019-2020, and 64.75% in 2021. Analyses assessing changes in age-appropriate full-vaccination coverage before and during the pandemic show a significant increase (OR: 1.8, 95% CI: 1.14-2.85). Our models also confirmed the presence of heterogeneity in full vaccination between health administrative districts. The pandemic could have increased inequities in infant vaccination completion between these districts. The analyses suggest no disruption in age-appropriate full vaccination due to COVID-19. Our findings from our sensitivity analyses to examine trends since 2010 did not show any steady trends. CONCLUSION: Our findings in Burkina Faso do not support the predicted detrimental effects of COVID-19 on the immunization schedule for infants in low- and middle-income countries. Analyses comparing 2019 and 2021 show an improvement in age-appropriate full vaccination. Regardless of achieving and sustaining vaccination coverage levels in Burkina Faso, this should remain a priority for health systems and political agendas.

Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies.

PURPOSE: To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies. MATERIALS AND METHODS: The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE. CONCLUSIONS: BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.

No child left behind: Building a comprehensive sickle cell disease care oasis in the Lake County, Indiana care desert.

BACKGROUND: Sickle cell disease (SCD) leads to end-organ damage and shortened life expectancy. The second highest incidence of SCD in Indiana is in Lake County, but until 2017, there was no SCD expert within 65 miles. The Indiana Hemophilia and Thrombosis Center (IHTC) developed the Sickle Care coordination OutReach and Education (SCORE) program in 2017 to bring high-quality, guideline-based care to children with SCD. PROCEDURE: The St. Vincent IRB deemed this retrospective analysis of SCORE clinic care from 2017 to 2020 exempt. Data on the number of transcranial Dopplers (TCD) performed, HU dosing escalation, and vaccine rates were collected along with the number of school and home visits completed. RESULTS: Fifty-three children, adolescents, and young adults completed 288 SCORE clinic visits during the study period; over 75% completed at least three clinic visits. Mean HU dose increased significantly with SCORE clinic care. TCD screening rates increased every year starting in 2018 through 2020 when we added local care coordination. One hundred seventy-three vaccines were administered in SCORE outreach clinics. The PPSV23 vaccines had a 100% acceptance rate, and seasonal influenza had a 75.8% acceptance rate. CONCLUSION: Access to care coordination services and local hematology specialty care alleviates barriers to care and enables comprehensive SCD care delivery to children in need. Prior to the establishment of the SCORE clinic, 75% of children in Lake County were not receiving recommended stroke screening. The SCORE clinic model demonstrates feasibility and impact when delivering on the promise of high-quality care for children with SCD.

Screening for functional transcriptional and splicing regulatory variants with GenIE.

Genome-wide association studies (GWAS) have identified numerous genetic loci underlying human diseases, but a fundamental challenge remains to accurately identify the underlying causal genes and variants. Here, we describe an arrayed CRISPR screening method, Genome engineering-based Interrogation of Enhancers (GenIE), which assesses the effects of defined alleles on transcription or splicing when introduced in their endogenous genomic locations. We use this sensitive assay to validate the activity of transcriptional enhancers and splice regulatory elements in human induced pluripotent stem cells (hiPSCs), and develop a software package (rgenie) to analyse the data. We screen the 99% credible set of Alzheimer's disease (AD) GWAS variants identified at the clusterin (CLU) locus to identify a subset of likely causal variants, and employ GenIE to understand the impact of specific mutations on splicing efficiency. We thus establish GenIE as an efficient tool to rapidly screen for the role of transcribed variants on gene expression.

Using experience to create evidence: a mixed methods process evaluation of the new free family planning policy in Burkina Faso.

BACKGROUND: In 2019, Burkina Faso was one of the first countries in Sub-Saharan Africa to introduce a free family planning (FP) policy. This process evaluation aims to identify obstacles and facilitators to its implementation, examine its coverage in the targeted population after six months, and investigate its influence on the perceived quality of FP services. METHODS: This process evaluation was conducted from November 2019 through March 2020 in the two regions of Burkina Faso where the new policy was introduced as a pilot. Mixed methods were used with a convergent design. Semi-directed interviews were conducted with the Ministry of Health (n = 3), healthcare workers (n = 10), and women aged 15-49 years (n = 10). Surveys were also administered to the female members of 696 households randomly selected from four health districts (n = 901). RESULTS: Implementation obstacles include insufficient communication, shortages of consumables and contraceptives, and delays in reimbursement from the government. The main facilitators were previous experience with free healthcare policies, good acceptability in the population, and support from local associations. Six months after its introduction, only 50% of the surveyed participants knew about the free FP policy. Higher education level, being sexually active or in a relationship, having recently seen a healthcare professional, and possession of a radio significantly increased the odds of knowing. Of the participants, 39% continued paying for FP services despite the new policy, mainly because of stock shortages forcing them to buy their contraceptive products elsewhere. Increased waiting time and shorter consultations were also reported. CONCLUSION: Six months after its introduction, the free FP policy still has gaps in its implementation, as women continue to spend money for FP services and have little knowledge of the policy, particularly in the Cascades region. While its use is reportedly increasing, addressing implementation issues could further improve women's access to contraception.

Burkina Faso is one of the first countries in sub-Saharan Africa to remove user fees for family planning services. Introduced as a pilot in June 2019, this policy covers the main costs, including the contraceptives, for all women of reproductive age (15­49 years old). We conducted a study to find out how the implementation of this new policy was going. In particular, we wanted to know what might be limiting or facilitating the successful implementation of the policy in a rural community. Through interviews with health staff and women, we found that about half of the women did not even know that family planning was now free, even though it had been free for more than six months. In addition, there were problems in the supply chain, which meant that contraceptive methods may have become free, but they were no longer available. On the other hand, the new policy has been generally well received by the public: previous similar initiatives seem to have facilitated implementation, as have awareness campaigns conducted by non-governmental organizations. With this information, the new policy can be improved to further enhance women's access to contraceptive methods in rural Burkina Faso.

Optic neuritis with potential for poor outcome.

The Optic Neuritis Treatment Trial previously reported that corticosteroids accelerated visual recovery in optic neuritis (ON) without improving outcome. This finding related largely to multiple sclerosis (MS), and subsequently neurologists tended to await spontaneous recovery in ON. Since then, non-MS cases of ON have been identified with antibodies to aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG). These disorders can closely mimic multiple sclerosis-associated or idiopathic demyelinating optic neuritis (MS/IDON) initially but risk a worse visual outcome. Scrutinising the clinical features and neuroimaging often enables differentiation between MS/IDON and other causes of ON. Early treatment with high-dose corticosteroids is an important determinant of visual outcome in non-MS/IDON. Prompt use of plasma exchange may also save sight. In this review, we contrast the presentations of myelin oligodendrocyte glycoprotein associated optic neuritis (MOG-ON) and aquaporin 4 associated optic neuritis (AQP4-ON) with MS/IDON and provide an approach to acute management while awaiting results of antibody testing.

Dr Gordon Plant's Festschrift Tidings.

We came together in March 2021 for a joyous celebration of Dr Gordon Plant's incredible career. This is a report of the meeting tidings.

How we coordinate care for uninsured children with nonmalignant hematologic disorders.

Providing medical care for uninsured children with nonmalignant hematologic diagnoses presents unique challenges to medical providers and multidisciplinary staff. Financial and psychosocial stressors can hinder optimal care of the uninsured child. Maximizing coverage of medical costs through patient enrollment in state and charity care programs and capitalizing upon community partnerships can help providers achieve comprehensive care for these children. Collaboration between primary care providers, subspecialists, and multidisciplinary teams can be optimized to facilitate provision of hematology care for uninsured children. We detail our experience in establishing these collaborations to improve access to subspecialty care for children with nonmalignant hematologic disorders.

Differences in Quit Attempts, Successful Quits, Methods, and Motivations in a Longitudinal Cohort of Adult Tobacco Users by Sexual Orientation.

INTRODUCTION: Sexual minority (SM) tobacco users are less likely to successfully quit than heterosexuals, yet little evidence describes cessation behaviors in this population over time. AIMS AND METHODS: Our study investigated quit motivations, attempts, and methods in a longitudinal cohort of adult tobacco users by sexual orientation. Participants (N = 1177) completed interviews every 6 months through 48 months and reported quit attempts (24-hour tobacco free), successful quits (7-day point prevalence abstinence), motivations, and methods. Chi-squared and Fisher's exact tests assessed differences by heterosexual and SM orientation, gender, and quit outcome (attempt-only vs. successful quit). RESULTS: Quit rates were similar for heterosexual and SM adults. Over half attempted to quit at least once over 48 months, but few remained abstinent (SM: 16.9%; heterosexual: 12.1%). Most used nicotine replacement therapy (SM: 31.9%; heterosexual: 26.1%) or tobacco product substitution (SM: 27.7%; heterosexual: 21.2%). Few used quitlines (SM: 4.3%; heterosexual: 1.3%) or Internet-based programs (SM: 6.4%; heterosexual: 1.3%). Quit motivations included health concerns, family, and physical fitness. Participants reporting a successful quit were more likely to report a household member quit smoking than 24-hour quit attempters. Among participants reporting a successful quit, more SM than heterosexual participants reported that a coworker quit smoking (55.6% vs. 33.1%, p = .009). CONCLUSIONS: We found few differences between heterosexual and SM tobacco users in our sample. Many repeatedly attempt to quit, yet few used evidence-based methods. Leveraging online quit programs, health messages, and family members in tailored cessation interventions may help SM and heterosexual tobacco users successfully quit. IMPLICATIONS: SM and heterosexual tobacco users evidenced few differences in quit behaviors. Over 4 years, a majority attempted to quit, with over a third making repeated quit attempts. Nicotine replacement therapy and tobacco product substitution were mostly used during quit attempts; however, more SM than heterosexual men reported using web-based quit programs. Personal health and family concerns were universal motivations to quit, yet SM women also cited physical fitness as a primary motivation. Tobacco users reporting that a household member stopped smoking were more likely to successfully quit. More SM than heterosexual men reported that a coworker quit smoking.

Postgraduate medical education quality metrics panels can be enhanced by including learner outcomes.

Postgraduate medical education (PME) quality assurance at Health Education England (HEE) currently relies upon survey data. As no one metric can reflect all aspects of training, and each has its limitations, additional metrics should be explored. At HEE (West Midlands), we explored the use of learner outcomes, speciality examination pass rates and Annual Review of Competence Progression (ARCP) outcomes, as quality metrics. Feedback received from our local Quality Forum of 40 senior educators frames the discussion through this paper. Overall, learner outcomes are useful quality metrics that add to survey data to provide a more comprehensive picture of PME quality. However, the utility of ARCP outcomes as quality metrics is currently limited by concerns regarding variations in ARCP practice between regions. To address these concerns, ARCPs need the same processes, rigour, scrutiny and investment as other high-stakes assessments. This will improve the reliability and validity of the ARCP as an assessment and improve the usefulness of ARCP outcomes as quality metrics. Research is required to determine the optimal combination of metrics to use in PME quality assurance and to appraise the validity and reliability of the ARCP as an assessment.

Colour-centred Release Hallucinations in a Patient with Early Parkinson's Disease and Unrecognised Autosomal Dominant Optic Atrophy.

Visual hallucinations in Parkinson's disease (PD) are usually attributed to medications and dysfunction in higher order sensory processing as the disease progresses. However deficits in visual processing, including colour discrimination, have been reported in early, untreated PD and it is unclear how these, along with co-morbid conditions affecting vision, could contribute to hallucinations. This case describes a 66-year-old otherwise fully independent woman with early, mild PD who presented with discrete episodes of unusual vivid hallucinations centred on colour. She was later found to have a subclinical colour deficiency in excess of her PD and, after reporting a lifelong history of poor vision in her father, tested positive for autosomal dominant optic atrophy. This case illustrates how a lifelong extrinsic deficiency in colour vision can interact with the effects of visual changes in early stage PD and medication to provoke colour hallucinations. It therefore emphasises the importance of full ophthalmological work up in similar cases where hallucinations are atypical and unexpected for the severity and stage of PD.

Outbreak of Respiratory Illness Associated With Human Adenovirus Type 7 Among Persons Attending Officer Candidates School, Quantico, Virginia, 2017.

A respiratory outbreak associated with human adenovirus type 7 (HAdV-7) occurred among unvaccinated officer candidates attending initial military training. Respiratory infections associated with HAdV-7 can be severe, resulting in significant morbidity. Genomic sequencing revealed HAdV-7d, a genome type recently remerging in the United States as a significant respiratory pathogen, following reports from Southeast Asia. Twenty-nine outbreak cases were identified; this likely represents an underestimate. Although the HAdV type 4 and 7 vaccine is currently given to US military enlisted recruit trainees, it is not routinely given to officer candidates. Administration of the HAdV type 4 and 7 vaccine may benefit this cohort.

Diagnosing uncertainty, producing neonatal abstinence syndrome.

The use of alcohol and other drugs during pregnancy is understood to be an important public health problem. One way in which this problem is expressed and responded to is via the identification and treatment of neonatal abstinence syndrome (NAS). In this article, we demonstrate how the processes of anticipating, identifying and responding to NAS are characterised by significant uncertainty among parents and health and social care practitioners. We draw on interviews with 16 parents who had recently had a baby at risk of NAS, and multidisciplinary focus groups with 27 health and social care professionals, held in Scotland, UK. NAS, and drug use in pregnancy, is a fraught and complex arena. Parents in the UK who use opioids risk losing custody of children, and must navigate a high degree of surveillance, governance and marginalisation. We suggest that considering NAS as a social diagnosis, further informed by Mol's political ontology of 'multiple' bodies/diseases, may help to produce clinical and social responses to uncertainty which avoid, rather than promote, further marginalisation of parents who use drugs. One such response is to develop a culture of relationship-based care which empowers both service providers and service users to challenge existing practice and decision-making.

Population Health Content in Entry-Level Occupational Therapy Programs.

IMPORTANCE: If occupational therapy is to play an important role in improving population health, it is important to understand how academic programs are preparing new occupational therapists for this role. OBJECTIVE: To determine current and desired coverage of population health concepts in entry-level occupational therapy programs. DESIGN: Online survey administered to occupational therapy program directors. SETTING: Higher education institutions. PARTICIPANTS: Survey invitations were sent to all 182 entry-level occupational therapy program directors in Spring 2018. MEASURES: Questionnaire responses were used to calculate current and desired curriculum coverage of 23 population health domains. RESULTS: Of 182 program directors, 60 (33.0%) responded. Respondents agreed that 21 of 23 population health domains should be included in entry-level occupational therapy programs, and 11 of the domains had moderate or better coverage in their current programs. The largest gaps between current and desired coverage were found in global health issues, population health informatics, environmental health, and organization of health systems. CONCLUSIONS AND RELEVANCE: Occupational therapy faculty can use these results to further develop the population health content of their programs. WHAT THIS ARTICLE ADDS: Although the occupational therapy profession advocates for the role of occupational therapists in the improvement of population health, little information is available about how to prepare new occupational therapists for this role. This study addresses this gap by presenting occupational therapy program directors' assessments of current and desired levels of population health content within their programs.

Functional analysis of AEBP2, a PRC2 Polycomb protein, reveals a Trithorax phenotype in embryonic development and in ESCs.

The Polycomb repressive complexes PRC1 and PRC2 are key mediators of heritable gene silencing in multicellular organisms. Here, we characterise AEBP2, a known PRC2 co-factor which, in vitro, has been shown to stimulate PRC2 activity. We show that AEBP2 localises specifically to PRC2 target loci, including the inactive X chromosome. Proteomic analysis confirms that AEBP2 associates exclusively with PRC2 complexes. However, analysis of embryos homozygous for a targeted mutation of Aebp2 unexpectedly revealed a Trithorax phenotype, normally linked to antagonism of Polycomb function. Consistent with this, we observe elevated levels of PRC2-mediated histone H3K27 methylation at target loci in Aebp2 mutant embryonic stem cells (ESCs). We further demonstrate that mutant ESCs assemble atypical hybrid PRC2 subcomplexes, potentially accounting for enhancement of Polycomb activity, and suggesting that AEBP2 normally plays a role in defining the mutually exclusive composition of PRC2 subcomplexes.