Epigenetic regulation of gene expression is an important mechanism in development and disease. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications for RNA and has been shown to play critical roles in processes such as embryo development, cancer, and stress responses. Our guests today investigate how m6A regulates X chromosome dosage compensation to ensure proper balance of gene expression from X chromosomes between sexes. X-chromosome dosage compensation is accomplished through two complementary mechanisms. First, X-chromosome inactivation (XCI) silences one of the two X chromosomes in female cells. Second, the remaining active X chromosome is transcriptionally upregulated so that its gene expression levels are balanced with those of the autosomes, a process known as X-to-autosome (X-to-A) compensation. The authors dissect the distinct contributions of m6A RNA methylation to XCI versus X-to-A compensation across multiple embryonic lineages, providing deeper insights into the epigenetic regulation of early development.

The human intestinal epithelial barrier comprises diverse proliferative, secretory and absorptive cell types that facilitate nutrient digestion and absorption and protect against harmful environmental agents. The barrier and its function can vary between individuals due to genetic differences thus impact processes such as digestion, drug metabolism, and drug sensitivity. Our guests today investigated the effect of diverse culture conditions on the cell type composition, gene expression profiles, and maturation status of human pluripotent stem cell-derived intestinal epithelial cells in three different model systems. Their research provides insight into the relevant conditions and systems for modeling specific intestinal functions and highlights the importance of personalized intestinal model systems.

The blood-brain barrier (BBB), formed by brain endothelial cells, pericytes, and astrocytes, is organized into a neurovascular unit that regulates the exchange of proteins between blood circulation and brain parenchyma. Human stem-cell-based models using brain endothelial cells are a powerful tool to investigate how disease-related conditions might affect the blood-brain barrier integrity. However, the cell type composition is critical to faithfully model transcytosis across the blood-brain barrier. Our guests today developed a blood-brain model using induced pluripotent stem cells (iPSCs)-derived endothelial cells with brain-specific identity. Using this model they were able to investigate how disease risk factors affect intracellular transport and reveal a new role for ApoE4 in the regulation of iron metabolism at the blood-brain barrier.