Sexually dimorphic gene expression emerges with embryonic genome activation and is dynamic throughout development (RNA-seq)

As sex determines mammalian development, understanding the nature and developmental dynamics of the sexually dimorphic transcriptome is important. To explore this, we generated 72 genome-wide RNA-seq profiles from mouse eight-cell embryos, late gestation and adult livers, together with 4 ground-state pluripotent embryonic (ES) cell lines from which we generated both RNA-seq and multiple ChIP-seq profiles. We complemented this with previously published data to yield 5 snap-shots of pre-implantation development, late-gestation placenta and somatic tissue and multiple adult tissues for integrative analysis. We define a high-confidence sex-dimorphic signature of 56 genes in eight-cell embryos. Sex-chromosome-linked components of this signature are largely conserved throughout pre-implantation development and ES cells, whilst the autosomal component is more dynamic. Sex-biased gene expression is reflected by enrichment for activating and repressive histone modifications. The eight-cell signature is largely non-overlapping with that defined from fetal liver, neither was it correlated with liver or other adult tissues analysed. Fetal and adult liver gene expression signatures are also substantially different, yet a core set of common genes showing modest dimorphic expression was identified. Dramatic sex-specific expression of olfactory receptors was found in fetal liver. Sex-biased expression differences unique to adult liver were enriched for growth hormone-responsiveness. The majority of sex-chromosome based differences identified from eight-cell embryos are also present in placenta but not somatic tissue at the same gestational age. This systematic study identifies three distinct phases of sex dimorphism throughout mouse development, and has significant implications for understanding the developmental origins of sex-specific phenotypes and disease in mammals. Examination of the sexual dimorphisim during developmental stages of 8 Cell, Es Cell, Fetal Liver and Adult Liver由于性别决定哺乳动物的发育进程，解析性别二态性转录组的本质与发育动态具有重要研究价值。为探究该科学问题，我们从小鼠八细胞胚胎、妊娠晚期肝脏及成年肝脏中获取了72份全基因组RNA测序（RNA-seq）样本，并构建了4株初始态多能胚胎干细胞（ES细胞）系，对其同时开展RNA-seq及多种染色质免疫沉淀测序（ChIP-seq）分析。我们结合已发表的公开数据，最终获得5套可用于整合分析的样本数据集，涵盖植入前发育、妊娠晚期胎盘、躯体组织及多种成年组织。我们鉴定出八细胞胚胎中由56个基因构成的高可信度性别二态性特征。该特征的性染色体连锁组分在植入前发育全程及ES细胞中均高度保守，而常染色体组分则呈现更强的动态性。性别偏向性基因表达可通过激活型与抑制型组蛋白修饰的富集得到反映。八细胞胚胎的性别二态性特征与胎肝中的特征基本无重叠，且与肝脏或其他分析的成年组织均无相关性。胎肝与成年肝脏的基因表达特征也存在显著差异，但我们仍鉴定出一组核心基因，其展现出温和的性别二态性表达模式。我们在胎肝中发现了嗅觉受体的显著性别特异性表达。成年肝脏特有的性别偏向表达差异则富集于生长激素响应相关通路。我们在八细胞胚胎中鉴定出的多数性染色体相关表达差异，在同妊娠龄的胎盘中同样存在，但在同期躯体组织中未检测到此类差异。本系统性研究明确了小鼠发育过程中三个截然不同的性别二态性阶段，对解析哺乳动物性别特异性表型与疾病的发育起源具有重要意义。本研究还针对八细胞、ES细胞、胎肝及成年肝脏的发育阶段开展了性别二态性分析。