HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements.

Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers. In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner. How this modification is established and maintained at enhancers in connection with transcription factors (TFs) remains unknown. Using analysis of genome-wide histone modifications, TF binding, chromatin accessibility and gene expression, we show that HNF4A is essential for an active chromatin state. Using HNF4A loss and gain of function experiments in vivo and in cell lines in vitro, we show that HNF4A affects H3K4me1, H3K27ac and chromatin accessibility, highlighting its contribution to the establishment and maintenance of a transcriptionally permissive epigenetic state. Mechanistically, HNF4A interacts with the mixed-lineage leukaemia 4 (MLL4) complex facilitating recruitment to HNF4A-bound regions. Our findings indicate that HNF4A enriches H3K4me1, H3K27ac and establishes chromatin opening at transcriptional regulatory regions.

Cell diversity and plasticity during atrioventricular heart valve EMTs.

Epithelial-to-mesenchymal transitions (EMTs) of both endocardium and epicardium guide atrioventricular heart valve formation, but the cellular complexity and small scale of this tissue have restricted analyses. To circumvent these issues, we analyzed over 50,000 murine single-cell transcriptomes from embryonic day (E)7.75 hearts to E12.5 atrioventricular canals. We delineate mesenchymal and endocardial bifurcation during endocardial EMT, identify a distinct, transdifferentiating epicardial population during epicardial EMT, and reveal the activation of epithelial-mesenchymal plasticity during both processes. In Sox9-deficient valves, we observe increased epithelial-mesenchymal plasticity, indicating a role for SOX9 in promoting endothelial and mesenchymal cell fate decisions. Lastly, we deconvolve cell interactions guiding the initiation and progression of cardiac valve EMTs. Overall, these data reveal mechanisms of emergence of mesenchyme from endocardium or epicardium at single-cell resolution and will serve as an atlas of EMT initiation and progression with broad implications in regenerative medicine and cancer biology.

Fetal liver development and implications for liver disease pathogenesis.

The metabolic, digestive and homeostatic roles of the liver are dependent on proper crosstalk and organization of hepatic cell lineages. These hepatic cell lineages are derived from their respective progenitors early in organogenesis in a spatiotemporally controlled manner, contributing to the liver's specialized and diverse microarchitecture. Advances in genomics, lineage tracing and microscopy have led to seminal discoveries in the past decade that have elucidated liver cell lineage hierarchies. In particular, single-cell genomics has enabled researchers to explore diversity within the liver, especially early in development when the application of bulk genomics was previously constrained due to the organ's small scale, resulting in low cell numbers. These discoveries have substantially advanced our understanding of cell differentiation trajectories, cell fate decisions, cell lineage plasticity and the signalling microenvironment underlying the formation of the liver. In addition, they have provided insights into the pathogenesis of liver disease and cancer, in which developmental processes participate in disease emergence and regeneration. Future work will focus on the translation of this knowledge to optimize in vitro models of liver development and fine-tune regenerative medicine strategies to treat liver disease. In this Review, we discuss the emergence of hepatic parenchymal and non-parenchymal cells, advances that have been made in in vitro modelling of liver development and draw parallels between developmental and pathological processes.

Signalling pathways and transcriptional regulators orchestrating liver development and cancer.

Liver development is controlled by key signals and transcription factors that drive cell proliferation, migration, differentiation and functional maturation. In the adult liver, cell maturity can be perturbed by genetic and environmental factors that disrupt hepatic identity and function. Developmental signals and fetal genetic programmes are often dysregulated or reactivated, leading to dedifferentiation and disease. Here, we highlight signalling pathways and transcriptional regulators that drive liver cell development and primary liver cancers. We also discuss emerging models derived from pluripotent stem cells, 3D organoids and bioengineering for improved studies of signalling pathways in liver cancer and regenerative medicine.

Factors Influencing Plastic Surgeons When Selecting New Colleagues.

INTRODUCTION: As plastic surgeons are continuing to form larger groups, it is essential to select candidates who will contribute to a positive work environment. This article shows which traits may be the most valuable when selecting candidates and in which ways a selection committee may want to focus their search. METHODS: For the study, the Canadian Society of Plastic Surgeons' members answered a survey containing questions about demographics, the factors which influence the selection process, and their hiring experiences. Responses were separated and compared in groups based on gender, practice type, group size, and years practising. Significance was established if P < .05 using the χ2 test. RESULTS: The most and least important factors regarding hiring a new group member were established. Statistically significant results were obtained between several different factors, including hiring a non-Canadian, the importance of the candidate's professional reputation, the number of publications by the candidate, and the presence or absence of program director letters. A majority (54%) of society members regret having hired a candidate, with the vast majority of these (75%) indicating personality and work ethic issues as opposite to professional skills as the uncomplimentary feature. CONCLUSION: This study has identified the key features which influence hiring new candidates. The need to develop a more efficient hiring process has been identified and has highlighted the difficulty faced by Canadian plastic surgery groups when recruiting new members.

Expression patterns of Yes-associated protein 1 in the developing mouse liver.

The Hippo signaling pathway regulates many cellular processes, but has been specifically associated with control organ size and tumor growth. Yes-associated protein 1 (YAP1) is a transcriptional cofactor, in the Hippo pathway, that regulates gene expression when localized in the nucleus. Elevated expression of YAP1 in adult mouse liver leads to hepatomegaly and can cause hepatocellular carcinoma; while the loss of function studies reveal its importance in regulating cholangiocyte development. Here, we report the expression of YAP1 in mouse embryonic and postnatal hepatic cells, using AFP-GFP transgenic mice to identify the hepatocyte lineage. At embryonic day (E) 8.5, YAP1 is highly expressed in the endoderm, but is not present in the nucleus. Between E9.5-12.5, hepatic cells display low levels of nuclear and non-nuclear YAP1. The nuclear expression of YAP1 is first detected in a small subset of hepatic cells starting at E13.5 when the hepatoblasts begin to differentiate into hepatocytes and cholangiocytes. At E18.5, nuclear YAP1 is nearly undetectable in hepatoblasts and hepatocytes, but enriched within the nuclei of cholangiocytes. These levels remain similar postnatally, consistent with the role of YAP1 in cholangiocyte specification and maintenance.