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Background: Lung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively. Methods: Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data. Results: We found that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue and tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also discovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, including AKT2 and KRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database. Conclusions: These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management. Plain English Summary: Lung adenocarcinoma (LUAD) is a disease that affects males and females differently. Biological sex not only influences chances of developing the disease, but also how the disease progresses and how effective various therapies may be. We analyzed sex-specific gene regulatory networks consisting of transcription factors and the genes they regulate in both healthy lung tissue and in LUAD and identified sex-biased differences. We found that genes associated with cell proliferation, immune response, and drug metabolism are differentially targeted by transcription factors between males and females. We also found that several genes that are drug targets in LUAD, are also regulated differently between males and females. Importantly, these differences are also influenced by an individual's smoking history. Extending our analysis using a drug repurposing tool, we found candidate drugs with evidence that they might work better for one sex or the other. These results demonstrate that considering the differences in gene regulation between males and females will be essential if we are to develop precision medicine strategies for preventing and treating LUAD. Highlights: Genes associated with cell proliferation, immune response, and drug metabolism are differentially targeted by transcription factors between males and females in healthy lung tissue and lung adenocarcinoma samples. Gene regulatory differences between males and females are also affected by an individual's history of smoking. Significant sex bias exists in transcription factor targeting patterns of several clinically actionable oncogenes and tumor suppressor genes including AKT2 and KRAS. Analyzing sex-biased gene regulatory networks in lung adenocarcinoma identified small-molecule cancer therapeutics with potential sex-specific efficacy, underscoring the importance of considering sex-specific gene regulation in precision medicine. [ABSTRACT FROM AUTHOR]

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field. Here, we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV , a 1,454,621-bp yeast chromosome resulting from extensive genome streamlining and modification. We developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction. Besides the drastic sequence changes, we further manipulated the 3D structure of synIV to explore spatial gene regulation. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of synIV sheds light on higher-order architectural design of the synthetic genomes. [Display omitted] • De novo synthesis of the largest eukaryotic chromosome, synIV • SynIV has 3D structure similar to native chrIV , despite thousands of changes • "Inside-out" intranuclear restructuring of synIV yields minor transcriptional changes • Multipoint tethering synIV to nuclear membrane pervasively represses synIV transcription Zhang et al. synthesized a 1.45-Mb extensively modified yeast chromosome from scratch. The gene position/expression relationship was probed by turning synIV inside-out, exchanging the positions of centromeres and telomeres, with little impact on the transcriptome. When tethering synIV to the inner nuclear membrane, transcription throughout synIV was reduced. [ABSTRACT FROM AUTHOR]