Extensive chromatin reprogramming occurs at fertilization and is thought to be under the control of maternal factors, but the underlying mechanisms remain poorly understood. We report that maternal Hira, a chaperone for the histone variant H3.3, is required for mouse development past the zygote stage. Male pronucleus formation is inhibited upon deletion of Hira due to a lack of nucleosome assembly in the sperm genome. Hira mutant oocytes are incapable of developing parthenogenetically, indicative of a role for Hira in the female genome. Both parental genomes show highly reduced levels of DNA replication and transcription in the mutants. It has long been thought that transcription is not required for zygote development. Surprisingly, we found that Hira/H3.3-dependent transcription of ribosomal RNA is required for first cleavage. Our results demonstrate that Hira-mediated H3.3 incorporation is essential for parental genome reprogramming and reveal an unexpected role for rRNA transcription in the mouse zygote.

Many studies have evaluated the effectiveness of alcohol screening and brief intervention (SBI) but most of them have reported substantial loss to follow-up without investigating the characteristics of those lost to follow-up. We examined the association between Alcohol Use Disorders Identification Test (AUDIT) scores, readiness-to-change scores and the demographic factors with lost to follow-up. This retrospective study compared demographic characteristics, AUDIT and readiness-to-change scores for 190 lost to follow-up patients to 221 completed follow-up patients who participated in SBI in the Emergency Department between June 2006 and May 2007. Comparing the association between baseline characteristics and completed follow-up rate, those 30–39, 40–49 and 50 years and older had 0.46 (95% CI 0.32–0.91), 0.49 (95% CI 0.29–0.90) and 0.58 (95%CI 0.22–0.79) lower odds of completing follow-up, respectively, in comparison to those 18–29 years of age. The loss to follow-up group reported more negative consequences of alcohol and binge drinking than the completed follow-up group (p = 0.04). Using logistic regression, patients who experienced more negative effects of alcohol had 0.87 lower odds of completing follow-up (95% CI 0.79–0.96). The patients lost to follow-up in this study were significantly different in age and alcohol drinking habits compared to those completed follow-ups. It is important to consider differential loss to follow-up in assessing the validity and generalizability of intervention studies. This could help in tailoring methods of approaching patients based on target population characteristics.

The human naive pluripotent stem cell (PSC) state, corresponding to a pre-implantation stage of development, has been difficult to capture and sustain in vitro. We report that the Hippo pathway effector YAP is nuclearly localized in the inner cell mass of human blastocysts. Overexpression of YAP in human embryonic stem cells (ESCs) and induced PSCs (iPSCs) promotes the generation of naive PSCs. Lysophosphatidic acid (LPA) can partially substitute for YAP to generate transgene-free human naive PSCs. YAP- or LPA-induced naive PSCs have a rapid clonal growth rate, a normal karyotype, the ability to form teratomas, transcriptional similarities to human pre-implantation embryos, reduced heterochromatin levels, and other hallmarks of the naive state. YAP/LPA act in part by suppressing differentiation-inducing effects of GSK3 inhibition. CRISPR/Cas9-generated YAP(-/-) cells have an impaired ability to form colonies in naive but not primed conditions. These results uncover an unexpected role for YAP in the human naive state, with implications for early human embryology.