Transcription factor antagonism regulates heterogeneity in embryonic stem cell states.

Gene expression heterogeneity underlies cell states and contributes to developmental robustness. While heterogeneity can arise from stochastic transcriptional processes, the extent to which it is regulated is unclear. Here, we characterize the regulatory program underlying heterogeneity in murine embryonic stem cell (mESC) states. We identify differentially active and transcribed enhancers (DATEs) across states. DATEs regulate differentially expressed genes and are distinguished by co-binding of transcription factors Klf4 and Zfp281. In contrast to other factors that interact in a positive feedback network stabilizing mESC cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of factor binding to DATEs dampens variation in gene expression, and factor loss alters kinetics of switching between states. These results show antagonism between factors at enhancers results in gene expression heterogeneity and formation of cell states, with implications for the generation of diverse cell types during development.

Impact of Well-being Interventions for Siblings of Children and Young People with a Chronic Physical or Mental Health Condition: A Systematic Review and Meta-Analysis.

Siblings of children and young people with a chronic illness are at increased risk of poor psychological functioning. A number of studies have attempted to implement and evaluate interventions targeting the psychological well-being of this at-risk group. This systematic review summarises the evidence regarding psychological functioning of siblings following an intervention targeting their well-being. The meta-analysis considered behaviour and knowledge, two of the most frequently studied outcomes. The following databases were used: PsycINFO, EMBASE, CINAHL, PubMed, Scopus and Web of Science. Seventeen studies were eligible to be included in the systematic review and eight in the meta-analysis. Results from the systematic review reflected the inconsistency of intervention evaluations in this area with a high level of heterogeneity and a total of 23 outcomes considered across the 17 included studies. The meta-analysis estimated effect sizes using a standardised mean difference (SMD) approach. Pre-post analysis suggested significant improvement in behavioural outcomes and knowledge of their sibling's health conditions with a SMD of - 0.44 [95% CI (- 0.6, - 0.29); p = 0.000] and 0.69 [(95% CI = 0.42, 0.96); p = 0.000], respectively. The SMD was not significant for behavioural outcomes when considering treatment-control studies. In conclusion, the findings suggest interventions for well-being have a positive effect on the psychological functioning of siblings of children and young people with a chronic illness, but their specificity needs to be established. There is a need for further, more methodologically robust research in this area.