Xiong Lingyun, Liu Jing, Han Seung Yub, Koppitch Kari, Guo Jin-Jin, Rommelfanger Megan, Gao Fan, Hallgrimsdottir Ingileif B, Pachter Lior, Kim Junhyong, MacLean Adam L, McMahon Andrew P
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.
Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
bioRxiv. 2023 May 25:2023.05.06.539585. doi: 10.1101/2023.05.06.539585.
Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.
哺乳动物的器官在两性之间表现出不同的生理机能、疾病易感性和损伤反应。在小鼠肾脏中，性二态性基因活性图谱主要定位于近端小管（PT）段。大量RNA测序数据表明，在性腺控制下，出生后4周和8周时就已出现性别差异。激素注射研究以及雄激素和雌激素受体的基因敲除研究表明，雄激素受体（AR）介导的PT细胞基因活性调节为调控机制。有趣的是，热量限制会使雄性肾脏出现雌性化特征。单核多组学分析确定了小鼠肾脏中PT对AR活性反应的假定顺式调控区域和协同因子。在人类肾脏中，一组有限的基因显示出保守的性连锁调控，而对小鼠肝脏的分析则突出了性二态性基因表达调控中的器官特异性差异。这些发现引发了关于性二态性基因活性进化、生理意义以及疾病和代谢联系的有趣问题。
