The H2Bub1-deposition complex is required for human and mouse cardiogenesis.

De novo variants affecting monoubiquitylation of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation, cilia function, post-natal cardiomyocyte maturation and transcriptional elongation. However, how H2Bub1 affects cardiogenesis is unknown. We show that the H2Bub1-deposition complex (RNF20-RNF40-UBE2B) is required for mouse cardiogenesis and for differentiation of human iPSCs into cardiomyocytes. Mice with cardiac-specific Rnf20 deletion are embryonic lethal and have abnormal myocardium. We then analyzed H2Bub1 marks during differentiation of human iPSCs into cardiomyocytes. H2Bub1 is erased from most genes at the transition from cardiac mesoderm to cardiac progenitor cells but is preserved on a subset of long cardiac-specific genes. When H2Bub1 is reduced in iPSC-derived cardiomyocytes, long cardiac-specific genes have fewer full-length transcripts. This correlates with H2Bub1 accumulation near the center of these genes. H2Bub1 accumulation near the center of tissue-specific genes was also observed in embryonic fibroblasts and fetal osteoblasts. In summary, we show that normal H2Bub1 distribution is required for cardiogenesis and cardiomyocyte differentiation, and suggest that H2Bub1 regulates tissue-specific gene expression by increasing the amount of full-length transcripts.

Social and Demographic Factors Impact Shoulder Stabilization Surgery in Anterior Glenohumeral Instability.

Purpose: To assess independent predictors of surgery after an emergency department visit for shoulder instability, including patient-related and socioeconomic factors. Methods: Patients presenting to the emergency department were identified in the New York Statewide Planning and Research Cooperative System database from 2015 to 2018 by International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for anterior shoulder dislocation or subluxation. All shoulder stabilization procedures in the outpatient setting were identified using Current Procedural Terminology codes (23455, 23460, 23462, 23466, and 29806). A multivariable logistic regression was performed to assess the impact of patient factors on the likelihood of receiving surgery. The variables included in the analysis were age, sex, race, social deprivation, Charlson Comorbidity Index, recurrent dislocation, and primary insurance type. Results: In total, 16,721 patients with a shoulder instability diagnosis were included in the analysis and 1,028 (6.1%) went on to have surgery. Patients <18 years old (odds ratio [OR] 8.607, P < .0001), those with recurrent dislocations (OR 2.606, P < .0001), or worker's compensation relative to private insurance (OR 1.318, P = .0492) had increased odds of receiving surgery. Hispanic (OR 0.711, P = .003) and African American (OR 0.63, P < .0001) patients had decreased odds of surgery compared with White patients. Patients with Medicaid (OR 0.582, P < .0001) or self-pay (OR 0.352, P < .0001) insurance had decreased odds of undergoing surgery relative to privately insured patients. Patients with greater levels of social deprivation (OR 0.993, P < .0001) also were associated with decreased odds of surgery. Conclusions: Anterior glenohumeral instability and subsequent stabilization surgery is associated with disparities among patient race, primary insurance, and social deprivation. Clinical Relevance: Considering the relationship between differential care and health disparities, it is critical to define and increase physician awareness of these disparities to help ensure equitable care.

A core of differentially methylated CpG loci in gMDSCs isolated from neonatal and adult sources.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs), which include monocytic (mMDSCs) and granulocytic (gMDSCs) cells, are an immunosuppressive, heterogeneous population of cells upregulated in cancer and other pathologic conditions, in addition to normal conditions of stress. The origin of MDSCs is debated, and the regulatory pattern responsible for gMDSC differentiation remains unknown. Since DNA methylation (DNAm) contributes to lineage differentiation, we have investigated whether it contributes to the acquisition of the gMDSC phenotype. RESULTS: Using the Illumina EPIC array to measure DNAm of gMDSCs and neutrophils from diverse neonatal and adult blood sources, we found 189 differentially methylated CpGs between gMDSCs and neutrophils with a core of ten differentially methylated CpGs that were consistent across both sources of cells. Genes associated with these loci that are involved in immune responses include VCL, FATS, YAP1, KREMEN2, UBTF, MCC-1, and EFCC1. In two cancer patient groups that reflected those used to develop the methylation markers (head and neck squamous cell carcinoma (HNSCC) and glioma), all of the CpG loci were differentially methylated, reaching statistical significance in glioma cases and controls, while one was significantly different in the smaller HNSCC group. CONCLUSIONS: Our findings indicate that gMDSCs have a core of distinct DNAm alterations, informing future research on gMDSC differentiation and function.