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Regulation of mitochondrial biogenesis and respiration is a complex process that involves several signaling pathways and transcription factors as well as communication between the nuclear and mitochondrial genomes. Here we show that decreased expression of histones or a defect in nucleosome assembly in the yeast Saccharomyces cerevisiae results in increased mitochondrial DNA (mtDNA) copy numbers, oxygen consumption, ATP synthesis, and expression of genes encoding enzymes of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). The metabolic shift from fermentation to respiration induced by altered chromatin structure is associated with the induction of the retrograde (RTG) pathway and requires the activity of the Hap2/3/4/5p complex as well as the transport and metabolism of pyruvate in mitochondria. Together, our data indicate that altered chromatin structure relieves glucose repression of mitochondrial respiration by inducing transcription of the TCA cycle and OXPHOS genes carried by both nuclear and mitochondrial DNA.

Objective: Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development and often present in utero as pleural effusion, chylothorax, nuchal and soft tissue edema, ascites, or hydrops. Many LAs are caused by single nucleotide variants, which are not detected on routine prenatal testing.Methods: Demographic data were compared between two subcohorts, those with clinically significant fetal edema (CSFE) and isolated fetal edema. A targeted variant analysis of LA genes was performed using American College of Medical Genetics criteria on whole exome sequencing (WES) data generated for 71 fetal edema cases who remained undiagnosed after standard workup.Results: CSFE cases had poor outcomes, including preterm delivery, demise, and maternal preeclampsia. Pathogenic and likely pathogenic variants were identified in 7% (5/71) of cases, including variants in RASopathy genes, RASA1, SOS1, PTPN11, and a novel PIEZO1 variant. Variants of uncertain significance (VOUS) were identified in 45% (32/71) of cases. In CSFEs, VOUS were found in CELSR1, EPHB4, TIE1, PIEZO1, ITGA9, RASopathy genes, SOS1, SOS2, and RAF1.Conclusions: WES identified pathogenic and likely pathogenic variants and VOUS in LA genes in 51% of fetal edema cases, supporting WES and expanded hydrops panels in cases of idiopathic fetal hydrops and fluid collections. Key pointsWhat's known on this topic? � Congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development.� Variants in several genes are known to cause LAs though many of variants remain unknown.� The full contribution of LA genes to fetal hydrops and nuchal edema remains unknown.

Osseous metastasis (OM) in ovarian cancer (OC) are rare, with an incidence ranging from 0.8% to 2.6%, and are associated with poor prognosis. The available literature on their management and associated complications is scarce.We report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial OC (EOC) who presented with neck pain. Imaging revealed multiple cervical spine metastases with left vertebral artery encasement and concurrent C1 lateral mass compression fracture, without neurological deficit, requiring occiput to C2 posterior instrumentation and fusion.Early OM may be associated with shorter overall survival, and survival after OM diagnosis is on the order of months. Management of OM should include a multidisciplinary team and may require surgical stabilization in addition to systemic chemotherapy, local radiotherapy, and osteoclast inhibitors.

Acetyl‐CoA is a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Concentration of acetyl‐CoA affects histone acetylation and links intermediary metabolism and transcriptional regulation. Transcriptional activation is typically associated with increased acetylation of promoter histones. However, this paradigm does not apply to transcriptional activation of all genes. Here we show that genes required for mitochondrial biogenesis are repressed by histone acetylation. During exponential growth of budding yeast cells in rich, glucose‐based medium, mitochondrial biogenesis is repressed and cells metabolize glucose predominantly by glycolysis. Under these conditions, the cellular level of acetyl‐CoA is high and global histone acetylation is also high. When glucose becomes limiting, the cells enter diauxic shift, upregulate mitochondrial activity and switch metabolism from glycolysis to oxidative phosphorylation. This metabolic transition is associated with a decreased cellular level of acetyl‐CoA. To probe the role of global histone acetylation in regulation of mitochondrial biogenesis and activity, we characterized yeast mutants that express nonacetylatable versions of histones H3 and H4. These mutants displayed increased mitochondrial biogenesis and activity. Taken together, our results suggest a model in which decreased global histone acetylation signals decreased glucose availability and results in a metabolic switch from fermentation to oxidative phosphorylation. This work is supported by a grant from the NIH (GM106324).