Hepatic transcriptome of mice with a deletion of the miR-379/miR-410 cluster obtained 4h following a caesarean at embryonic day E19.5

In placental mammals, adaptation to extra-uterine life requires complex metabolic adjustments linked to the abrupt transition from the transplacental transfer of glucose toward the use of fat originating from the mother's milk as a major energy source. The study of a novel knock-out mouse model led us to identify the biological roles of the miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 cluster is the largest mammalian-specific miRNA cluster composed of 39 pre-miRNA and expressed from the maternally-inherited allele. We unexpectedly found that ~ 35% of heterozygous neonates with a maternal - but not paternal - deletion of the entire 40kb-long miRNA cluster die shortly after birth due to defects in the maintenance of energy homeostasis, as evidenced by impaired hepatic glycogenolysis, gluconeogenesis and ketogenesis. This maladaptive metabolic response is accompanied by profound changes in the neonatal hepatic gene expression program, notably a decrease in the activation of a large set of metabolic genes linked to lipid metabolism. Our study unveils essential roles for the miR-379/miR-410 cluster at the transition from fetal to postnatal life, revealing new layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on postnatal metabolic functions. Liver gene expression was measured in mice with a maternally-inherited deletion of the miR-379/miR-410 cluster and in wild-type littermates at embryonic day E19.5, 4h following the caesarean delivery (n=4 biological replicates per genotype)对于有胎盘哺乳动物而言，适应宫外生活需要复杂的代谢调控，该过程伴随葡萄糖经胎盘转运向以母乳来源脂肪作为主要能量来源的突然转变。本研究通过新型基因敲除小鼠模型（knock-out mouse model），鉴定出印记Dlk1-Dio3区域（imprinted Dlk1-Dio3 region）内的miR-379/miR-410基因簇（miR-379/miR-410 cluster）在该代谢转变过程中的生物学功能。miR-379/miR-410基因簇是目前已知最大的哺乳动物特异性miRNA基因簇，由39个前体miRNA组成，仅从母源遗传的等位基因表达。我们意外发现，约35%携带母源（而非父源）全长达40kb的该miRNA基因簇缺失的杂合子新生小鼠，会因能量稳态维持缺陷在出生后不久死亡，该缺陷可通过受损的肝糖原分解、糖异生及酮体生成得到验证。该适应不良的代谢反应伴随新生小鼠肝脏基因表达程序的显著改变，尤以与脂质代谢相关的大量代谢基因的激活水平下调为著。本研究揭示了miR-379/miR-410基因簇在胎儿向出生后生命阶段转变过程中的核心作用，阐明了Dlk1-Dio3区域内RNA介导的基因调控新层级，该调控可对出生后代谢功能施加亲本起源效应。本研究对携带母源miR-379/miR-410基因簇缺失的小鼠及其野生型同窝幼崽，在剖宫产术后4小时的胚胎发育第19.5天（E19.5）进行肝脏基因表达检测，每组基因型设置4个生物学重复（n=4 biological replicates per genotype）