Meiosis is a highly complex process significantly influenced by transcriptional regulation.However,studies on the mechanisms that govern transcriptomic changes during meiosis,especially in prophase I,are limited.Here,...Meiosis is a highly complex process significantly influenced by transcriptional regulation.However,studies on the mechanisms that govern transcriptomic changes during meiosis,especially in prophase I,are limited.Here,we performed single-cell ATAC-seq of human testis tissues and observed reprogramming during the transition from zygotene to pachytene spermatocytes.This event,conserved in mice,involved the deactivation of genes associated with meiosis after reprogramming and the activation of those related to spermatogenesis before their functional onset.Furthermore,we identified 282 transcriptional regulators(TRs)that underwent activation or deactivation subsequent to this process.Evidence suggested that physical contact signals from Sertoli cells may regulate these TRs in spermatocytes,while secreted ENHO signals may alter metabolic patterns in these cells.Our results further indicated that defective transcriptional reprogramming may be associated with non-obstructive azoospermia(NOA).This study revealed the importance of both physical contact and secreted signals between Sertoli cells and germ cells in meiotic progression.展开更多
Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation...Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing.We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(Hmgcs2)was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum.Reactive oxygen species(ROS)elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles,while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing(POA),which might be related to the activation of cellular endogenous antioxidant system.All these defects could be rescued by ketone body administration,which suppressed ROS-activated follicle apoptosis.Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.展开更多
Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, result...Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality;thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.展开更多
基金supported by the National Natural Science Foundation of China(82271645)National Key Research and Development Program of China(2021YFC2700200 to F.S.)。
文摘Meiosis is a highly complex process significantly influenced by transcriptional regulation.However,studies on the mechanisms that govern transcriptomic changes during meiosis,especially in prophase I,are limited.Here,we performed single-cell ATAC-seq of human testis tissues and observed reprogramming during the transition from zygotene to pachytene spermatocytes.This event,conserved in mice,involved the deactivation of genes associated with meiosis after reprogramming and the activation of those related to spermatogenesis before their functional onset.Furthermore,we identified 282 transcriptional regulators(TRs)that underwent activation or deactivation subsequent to this process.Evidence suggested that physical contact signals from Sertoli cells may regulate these TRs in spermatocytes,while secreted ENHO signals may alter metabolic patterns in these cells.Our results further indicated that defective transcriptional reprogramming may be associated with non-obstructive azoospermia(NOA).This study revealed the importance of both physical contact and secreted signals between Sertoli cells and germ cells in meiotic progression.
基金supported by the National Key Research and Development Program of China(2018YFC1004703).
文摘Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing.We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(Hmgcs2)was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum.Reactive oxygen species(ROS)elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles,while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing(POA),which might be related to the activation of cellular endogenous antioxidant system.All these defects could be rescued by ketone body administration,which suppressed ROS-activated follicle apoptosis.Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.
基金This work was supported by the National Natural Science Foundation of China(31530046)the National Science and Technology Major Project(SQ2018YFC100242).
文摘Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality;thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.