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The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.

This study investigated the links between naturalistically observed and self-reported interpersonal problems, diabetes management, and glucose levels in older adolescents and young adults with type 1 diabetes. Sixty-eight older adolescents and young adults (aged 17–20 years) participated in a cross-sectional study that consisted of three home visits and a daily diary segment. Participants wore the Electronically Activated Recorder (EAR) for four days to capture interpersonal problems and wore a continuous glucose monitor for blood glucose levels. Researchers also collected HbA1c values, conducted an interview to assess diabetes management, and collected participant-reported severity of interpersonal problems. High EAR-observed interpersonal problems were associated with poor diabetes management. Multiple regression analyses revealed that high EAR-observed interpersonal problems continued to explain variance in poor diabetes management after including self-reported interpersonal problems and covariates. These findings corroborate literature suggesting that negative interactions are associated with type 1 diabetes management. This study is the first to use the EAR to capture naturalistically observed interactions in this population and identify its utility beyond self-reports. These findings highlight the importance of considering naturalistically observed interactions when developing interventions to promote better diabetes management in older adolescents and young adults. [ABSTRACT FROM AUTHOR]

Subjective social status (SSS), the perception of one’s social standing compared to others in society, and socioeconomic status (SES) are interconnected but distinct determinants of health. Intermediary factors such as distress and health behaviors can contribute to this relationship. This pre-registered study hypothesized that, in the early months of the COVID-19 pandemic, nonspecific psychological distress would indirectly link SSS and SES to perceived changes in three health behaviors: sleep quality, physical activity, and alcohol consumption. Data from 412 US adults were collected from April to June 2020 through an online cross-sectional survey. Findings indicated that lower SSS was indirectly associated with lower current sleep quality, worsened sleep quality, and decreased physical activity since the pandemic onset via greater psychological distress. Path analyses controlled for age, gender, race, COVID-19-related worry, and shelter-in-place status. Results are discussed in light of findings from COVID-19 research and the broader literature on SES health disparities. [ABSTRACT FROM AUTHOR]

A mouse model was used to understand the process causing skewed X-chromosome inactivation (XCI) and null mutation. It was shown that the skewed XCI results from selection against ATR-X deficient cells at specific stages of development and differentiation in different tissues.

Background: John Henryism (JH) is a form of active high-effort coping. Low-socioeconomic status (SES) African Americans adopting JH to deal with structural racism and other chronic stressors might be more likely to display cardiovascular disease risk factors. Previous tests of this hypothesis have mostly focused on the moderating role of current SES and hypertension as the outcome variable. Furthermore, most of the previous work has been conducted among young and middle-aged adults. This study aimed at extending work on the JH hypothesis by testing the combined effect of JH and childhood SES on metabolic syndrome and systemic inflammation among African American older adults.Methods: One hundred seventy urban African American older adults (Mage = 67.64 years, 75.9% female) were recruited. Participants completed questionnaires assessing JH, childhood SES, and other variables used as covariates (ie, demographic information, chronic conditions, medication use, and health behaviors). Blood pressure, waist circumference, and blood were also collected. Triglycerides, high-density lipoprotein cholesterol, hemoglobin A1C, and C-reactive protein levels were measured from the blood samples.Results: JH was positively associated with metabolic syndrome symptoms among participants reporting low childhood SES levels, but not among those reporting high childhood SES levels. The same pattern did not emerge when we considered current SES. Similar patterns of results did not emerge as far as systemic inflammation was concerned.Conclusions: Our findings highlight the importance of considering the joint impact of objective conditions early in life and individual psychological proclivities in explaining increased risk for cardiovascular disease risk in this population. [ABSTRACT FROM AUTHOR]

Abstract Background In self-renewing, pluripotent cells, bivalent chromatin modification is thought to silence (H3K27me3) lineage control genes while 'poising' (H3K4me3) them for subsequent activation during differentiation, implying an important role for epigenetic modification in directing cell fate decisions. However, rather than representing an equivalently balanced epigenetic mark, the patterns and levels of histone modifications at bivalent genes can vary widely and the criteria for identifying this chromatin signature are poorly defined. Results Here, we initially show how chromatin status alters during lineage commitment and differentiation at a single well characterised bivalent locus. In addition we have determined how chromatin modifications at this locus change with gene expression in both ensemble and single cell analyses. We also show, on a global scale, how mRNA expression may be reflected in the ratio of H3K4me3/H3K27me3. Conclusions While truly 'poised' bivalently modified genes may exist, the original hypothesis that all bivalent genes are epigenetically premarked for subsequent expression might be oversimplistic. In fact, from the data presented in the present work, it is equally possible that many genes that appear to be bivalent in pluripotent and multipotent cells may simply be stochastically expressed at low levels in the process of multilineage priming. Although both situations could be considered to be forms of 'poising', the underlying mechanisms and the associated implications are clearly different.