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

• Published in: Endocrinology (Philadelphia) Vol. 160; no. 5; pp. 989 - 1007
• Main Authors: Melia, Tisha, Waxman, David J
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.05.2019; Endocrine Society
• Subjects: Ablation; Animals; Bias; Biochemistry; Chromatin; Circadian rhythms; Cluster Analysis; Collaborative Cross Mice; DNA binding proteins; Endocrinology; Enrichment; Female; Gender aspects; Gender differences; Gene expression; Gene Expression Profiling - methods; Gene Regulatory Networks - genetics; Genes; Genetic aspects; Genetic diversity; Genetic factors; Genetic research; Growth hormones; Health aspects; Heterogeneity; Hormones; Hypophysectomy; Identification and classification; Liver; Liver - metabolism; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Modules; Pituitary; Pituitary hormones; Pituitary Hormones - metabolism; Prejudice; Proteins; RNA; RNA, Long Noncoding - genetics; Sex; Sex differences; Sex differences (Biology); Sex discrimination; Sex Factors; Sexism; Somatotropin; Transcription factors; United States
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2018-00949

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.