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A Chinese family with matrilineally inherited obesity was assessed and its clinical, genetic, and molecular profiling was conducted. Obesity was observed in matrilineal relatives (3 out of 7) of a single generation (of 3 alive generations) in this family. On pedigree analysis and sequencing of their mitochondrial DNA (mtDNA), a novel homoplasmic mutation of the mitochondrial tRNACys gene (5802A>G) was identified in these individuals. This mutation correlated with a destabilized conserved base pair in this tRNA anticodon stem. Position 30 is known to be crucial for carrying out effective codon recognition and stability of tRNA. In accordance with the importance of this conserved site, we observed that the predicted structure of tRNACys with the mutation was noticeably remodeled in a molecular dynamics simulation when compared with the isoform of the wild-type. All other 46 mutations observed in the individual's mtDNA were known variants belonging to haplogroup D4. Thus, this is the first report that provides evidence of the association between a mutation in tRNA and an enhanced risk of maternally transmissible obesity, offering more insights into obesity and its underlying nature. [ABSTRACT FROM AUTHOR]

Steady-state gene expression across the cell cycle has been studied extensively. However, transcriptional gene regulation and the dynamics of histone modification at different cell-cycle stages are largely unknown. By applying a combination of global nuclear run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and histonemodification Chip sequencing (ChIP-seq), we depicted a comprehensive transcriptional landscape at the G0/G1, G1/S, and M phases of breast cancer MCF-7 cells. Importantly, GRO-seq and RNA-seq analysis identified different cell-cycle–regulated genes, suggesting a lag between transcription and steady-state expression during the cell cycle. Interestingly, we identified genes actively transcribed at earlyMphase that are longer in length and have low expression and are accompanied by a global increase in active histone 3 lysine 4 methylation (H3K4me2) and histone 3 lysine 27 acetylation (H3K27ac) modifications. In addition, we identified 2,440 cell-cycle–regulated enhancer RNAs (eRNAs) that are strongly associated with differential active transcription but not with stable expression levels across the cell cycle. Motif analysis of dynamic eRNAs predicted Kruppel-like factor 4 (KLF4) as a key regulator of G1/S transition, and this identification was validated experimentally. Taken together, our combined analysis characterized the transcriptional and histone-modification profile of the human cell cycle and identified dynamic transcriptional signatures across the cell cycle. [ABSTRACT FROM AUTHOR]

The authors convey their response to comments on a report about responsibility of the variant m.5082A>G in tRNA(Cys) for mitochondrial obesity. Topics mentioned include mitochondrial tRNA mutation site as risk factor related to obesity, the heteroplasmy rate of the m.5208A>G variant, and the principle that structure determines function.