Obesity promotes diverse pathologies, including atherosclerosis and dementia, which frequently involve vascular defects and endothelial cell (EC) dysfunction. Each organ has distinct EC subtypes, but whether ECs are differentially affected by obesity is unknown. Here we use single-cell RNA sequencing to analyze transcriptomes of ~375,000 ECs from seven organs in male mice at progressive stages of obesity to identify organ-specific vulnerabilities. We find that obesity deregulates gene expression networks, including lipid handling, metabolic pathways and AP1 transcription factor and inflammatory signaling, in an organ- and EC-subtype-specific manner. The transcriptomic aberrations worsen with sustained obesity and are only partially mitigated by dietary intervention and weight loss. For example, dietary intervention substantially attenuates dysregulation of liver, but not kidney, EC transcriptomes. Through integration with human genome-wide association study data, we further identify a subset of vascular disease risk genes that are induced by obesity. Our work catalogs the impact of obesity on the endothelium, constitutes a useful resource and reveals leads for investigation as potential therapeutic targets.

Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome–like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.

The functionality of chromatin is tightly regulated by post‐translational modifications that modulate transcriptional output from target loci. Among the post‐translational modifications of chromatin, reversible ε‐lysine acetylation of histone proteins is prominent at transcriptionally active genes. Lysine acetylation is catalyzed by lysine acetyltransferases (KATs), which utilize the central cellular metabolite acetyl‐CoA as their substrate. Among the KATs that mediate lysine acetylation, males absent on the first (MOF/KAT8) is particularly notable for its ability to acetylate histone 4 lysine 16 (H4K16ac), a modification that decompacts chromatin structure. MOF and its non‐specific lethal (NSL) complex members have been shown to localize to gene promoters and enhancers in the nucleus, as well as to microtubules and mitochondria to regulate key cellular processes. Highlighting their importance, mutations or deregulation of NSL complex members has been reported in both human neurodevelopmental disorders and cancer. Based on insight gained from studies in human, mouse, and Drosophila model systems, this review discusses the role of NSL‐mediated lysine acetylation in a myriad of cellular functions in both health and disease. Through these studies, the importance of the NSL complex in regulating core transcriptional and signaling networks required for normal development and cellular homeostasis is beginning to emerge.

DiGeorge syndrome, caused by a 22q11 microdeletion or mutation of the TBX1 gene, varies in severity greatly, even among monozygotic twins. Epigenetic phenomena have been invoked to explain phenotypic differences in individuals of identical genetic composition, although specific chromatin modifications relevant to DiGeorge syndrome are elusive. Here we show that lack of the histone acetyltransferase MOZ (MYST3/KAT6A) phenocopies DiGeorge syndrome, and the MOZ complex occupies the Tbx1 locus, promoting its expression and histone 3 lysine 9 acetylation. Importantly, DiGeorge syndrome-like anomalies are present in mice with homozygous mutation of Moz and in heterozygous Moz mutants when combined with Tbx1 haploinsufficiency or oversupply of retinoic acid. Conversely, a Tbx1 transgene rescues the heart phenotype in Moz mutants. Our data reveal a molecular mechanism for a specific chromatin modification of the Tbx1 locus intersecting with an environmental determinant, modeling variability in DiGeorge syndrome.