Hou Huayun, Uusküla-Reimand Liis, Makarem Maisam, Corre Christina, Saleh Shems, Metcalf Ariane, Goldenberg Anna, Palmert Mark R, Wilson Michael D
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Hum Mol Genet. 2017 Sep 15;26(18):3585-3599. doi: 10.1093/hmg/ddx246.
The timing of human puberty is highly variable, sexually dimorphic, and associated with adverse health outcomes. Over 20 genes carrying rare mutations have been identified in known pubertal disorders, many of which encode critical components of the hypothalamic-pituitary-gonadal (HPG) axis. Recent genome-wide association studies (GWAS) have identified more than 100 candidate genes at loci associated with age at menarche or voice breaking in males. We know little about the spatial, temporal or postnatal expression patterns of the majority of these puberty-associated genes. Using a high-throughput and sensitive microfluidic quantitative PCR strategy, we profiled the gene expression patterns of the mouse orthologs of 178 puberty-associated genes in male and female mouse HPG axis tissues, the pineal gland, and the liver at five postnatal ages spanning the pubertal transition. The most dynamic gene expression changes were observed prior to puberty in all tissues. We detected known and novel tissue-enhanced gene expression patterns, with the hypothalamus expressing the largest number of the puberty-associated genes. Notably, over 40 puberty-associated genes in the pituitary gland showed sex-biased gene expression, most of which occurred peri-puberty. These sex-biased genes included the orthologs of candidate genes at GWAS loci that show sex-discordant effects on pubertal timing. Our findings provide new insight into the expression of puberty-associated genes and support the possibility that the pituitary plays a role in determining sex differences in the timing of puberty.
人类青春期的时间高度可变、具有性别差异，且与不良健康后果相关。在已知的青春期疾病中已鉴定出20多个携带罕见突变的基因，其中许多基因编码下丘脑-垂体-性腺（HPG）轴的关键组成部分。最近的全基因组关联研究（GWAS）已在与女性初潮年龄或男性变声年龄相关的基因座上鉴定出100多个候选基因。我们对这些与青春期相关的大多数基因的空间、时间或出生后表达模式知之甚少。我们采用一种高通量且灵敏的微流控定量PCR策略，在跨越青春期转变的五个出生后年龄阶段，分析了178个与青春期相关基因的小鼠直系同源基因在雄性和雌性小鼠HPG轴组织、松果体及肝脏中的基因表达模式。在所有组织中，青春期前观察到最显著的基因表达变化。我们检测到已知和新的组织增强型基因表达模式，其中下丘脑表达的与青春期相关的基因数量最多。值得注意的是，垂体中超过40个与青春期相关的基因表现出性别偏向性基因表达，其中大部分发生在青春期前后。这些性别偏向性基因包括GWAS基因座上候选基因的直系同源基因，这些基因对青春期时间具有性别不一致的影响。我们的研究结果为与青春期相关基因的表达提供了新的见解，并支持垂体在决定青春期时间的性别差异中发挥作用的可能性。
