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Sex differences in liver gene expression are determined by pituitary growth hormone secretion patterns, which regulate sex-dependent liver transcription factors and establish sex-specific chromatin states. Hypophysectomy (hypox) identifies two major classes of liver sex-biased genes, defined by their sex-dependent positive or negative responses to pituitary hormone ablation. However, the mechanisms that underlie each hypox-response class are unknown. We sought to discover candidate, regulatory, long noncoding RNAs (lncRNAs) controlling responsiveness to hypox. We characterized gene structures and expression patterns for 15,558 mouse liver-expressed lncRNAs, including many sex-specific lncRNAs regulated during postnatal development or subject to circadian regulation. Using the high natural allelic variance of Diversity Outbred (DO) mice, we discovered tightly coexpressed clusters of sex-specific protein-coding genes (gene modules) in male and female DO liver. Remarkably, many gene modules were strongly enriched for sex-specific genes within a single hypox-response class, indicating that the genetic heterogeneity of DO mice encompasses responsiveness to hypox. Moreover, several distant gene modules were enriched for gene subsets of the same hypox-response class, highlighting the complex regulation of hypox-responsiveness. Finally, we identified eight sex-specific lncRNAs with strong negative regulatory potential, as indicated by their strong negative correlation of expression across DO mouse livers with that of protein-coding gene modules enriched for genes of the opposite sex bias and inverse hypox-response class. These findings reveal an important role for genetic factors in regulating responsiveness to hypox, and present testable hypotheses for the roles of sex-biased liver lncRNAs in controlling the sex-bias of liver gene expression.

Sex-Biased lncRNAs Inversely Correlate With Sex-Opposite Gene Coexpression Networks in Diversity Outbred Mouse Liver