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Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: Evidence for altered mitochondrial function and amino acid metabolism

ABSTRACT: Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: Evidence for altered mitochondrial function and amino acid metabolism

PROVIDER: PRJNA601215 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10894045_1.fastq.gz	Fastqsanger.gz
	SRR10894045_2.fastq.gz	Fastqsanger.gz
	SRR10894046_1.fastq.gz	Fastqsanger.gz
	SRR10894046_2.fastq.gz	Fastqsanger.gz
	SRR10894047_1.fastq.gz	Fastqsanger.gz

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Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: Evidence for altered mitochondrial function and amino acid metabolism

Project description:Numerous genetic manipulations that extend lifespan in mice have been discovered over the past two decades, the most robust of which has arguably been the down regulation of growth hormone (GH) signaling. However, while decreased GH signaling has been associated with improved health and lifespan, many of the underlying physiological changes and molecular mechanisms have yet to be elucidated. To this end, we have completed the first transcriptomic and metabolomic study on long-lived growth hormone releasing hormone knockout (GHRH-KO) and wild-type mice in brown adipose tissue (transcriptomics) and blood serum (metabolomics). We find that GHRH-KO mice have increased transcript levels of mitochondrial and amino acid genes with decreased levels of extracellular matrix genes. Concurrently, mitochondrial metabolites are differentially regulated in GHRH-KO. Furthermore, we find a strong signal of genotype-by-sex interactions, suggesting the sexes have differing physiological responses to GH deficiency. Overall, our results point towards a strong influence of mitochondrial metabolism in GHRH-KO mice which potentially is tightly intertwined with their extended lifespan phenotype.

2020-03-30 | GSE143672 | GEO

Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: evidence for altered mitochondrial function and amino acid metabolism.

Project description:Numerous genetic manipulations that extend lifespan in mice have been discovered over the past two decades, the most robust of which has arguably been the down regulation of growth hormone (GH) signaling. However, while decreased GH signaling has been associated with improved health and lifespan, many of the underlying physiological changes and molecular mechanisms associated with GH signaling have yet to be elucidated. To this end, we have completed the first transcriptomic and metabolomic study on long-lived growth hormone releasing hormone knockout (GHRH-KO) and wild-type mice in brown adipose tissue (transcriptomics) and blood serum (metabolomics). We find that GHRH-KO mice have increased transcript levels of mitochondrial and amino acid genes with decreased levels of extracellular matrix genes. Concurrently, mitochondrial metabolites are differentially regulated in GHRH-KO. Furthermore, we find a strong signal of genotype-by-sex interactions, suggesting the sexes have differing physiological responses to GH deficiency. Overall, our results point towards a strong influence of mitochondrial metabolism in GHRH-KO mice which potentially is tightly intertwined with their extended lifespan phenotype.

| S-EPMC7066919 | biostudies-literature

The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

Project description:The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

| PRJNA628688 | ENA

The histone H3-lysine 4-methyltransferase Mll4 governs the development of growth hormone-releasing hormone-producing neurons

Project description:In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltrasferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 is a critical regulator of the development of growth hormone-releasing hormone (GHRH)-producing neurons in the hypothalamus. The two distinct Mll4 mutant mouse models exhibited dwarfism, accompanied by impairment of developmental programs for GHRH-neurons. Our genome-wide studies revealed that, in the developing hypothalamus, Mll4 collaborates mainly with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 resulted in a marked reduction of transcriptionally active histone marks in the embryonic hypothalamus, which was rescued by treatment with the histone deacetylase inhibitor AR-42. Further, AR-42 treatment restored GHRH-neuronal production in Mll4 mutant mice. Together, our results suggest that the dysregulation of MLL4-directed epigenetic control of GHRH-neuronal genes is a substantial contributing factor to dwarfism in human KS.

2020-11-07 | GSE149439 | GEO

Insulin sensitivity in long-lived growth hormone-releasing hormone knockout mice.

Project description:Our previous studies showed that loss-of-function mutation of growth hormone releasing hormone (GHRH) results in increased longevity and enhanced insulin sensitivity in mice. However, the details of improved insulin action and tissue-specific insulin signaling are largely unknown in this healthy-aging mouse model. We conducted hyperinsulinemic-euglycemic clamp to investigate mechanisms underlying enhanced insulin sensitivity in growth hormone (GH) deficient mice. Further, we assessed in vivo tissue-specific insulin activity via activation of PI3K-AKT and MAPK-ERK1/2 cascades using western blot. Clamp results showed that the glucose infusion rate required for maintaining euglycemia was much higher in GHRH-/- mice compared to WT controls. Insulin-mediated glucose production was largely suppressed, whereas glucose uptake in skeletal muscle and brown adipose tissue were significant enhanced in GHRH-/- mice compared to WT controls. Enhanced capacity of insulin-induced activation of the PI3K-AKT and MAPK-ERK1/2 signaling were observed in a tissue-specific manner in GHRH-/- mice. Enhanced systemic insulin sensitivity in long-lived GHRH-/- mice is associated with differential activation of insulin signaling cascades among various organs. Improved action of insulin in the insulin sensitive tissues is likely to mediate the prolonged longevity and healthy-aging effects of GH deficiency in mice.

| S-EPMC7585079 | biostudies-literature

Placenta and uterus transcriptomes from transgenic mice expressing human corticotropin-releasing hormone in placenta

Project description:Placenta and uterus transcriptomes from transgenic mice expressing human corticotropin-releasing hormone in placenta

| PRJNA485077 | ENA

Regulatory Architecture of the LβT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone

Project description:Regulatory Architecture of the LβT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone

| PRJNA397847 | ENA

Placenta and uterus transcriptomes from transgenic mice expressing human corticotropin-releasing hormone in placenta

Project description:Purpose: Parturition is delayed by approximately 12 hours in transgenic mice expressing human corticotropin-releasing hormone (CRH) in placenta. The goal of the study was to identify the pathways in reproductive tissues (uterus and placenta) altered by placental expression of human CRH. Methods: Human BAC RP11-366K18 (CHORI) containing human CRH and cis-regulatory region was inserted into the mouse genome by microinjection and random integration to create the BAC1 line. The CRISPR/Cas9 system was used to delete a CRH regulatory element from the BAC1 line to create the CR1 line, eliminating expression of CRH in placenta. Total expression of uterus and placenta by RNA-seq at embryonic day 18.5 were compared between BAC1, CR1, and nontransgenic mice. Results: Genes known to be associated with luteolysis and initiation of parturition (Cav1, Gja1, Oxtr, Ptgs1, Ptgs2) were not differentially expressed in uterus of this model. Conclusions: CRH-mediated delay of parturition is likely independent of luteolysis.

2018-08-09 | GSE118283 | GEO

Gene expression of mouse gonadotropin-releasing hormone neurons from male and female mice

Project description:Background: Gonadotropin-releasing hormone (GnRH) neurons play a pivotal role in regulation of the hypothalamic-pituitary gonadal axis in a sex-specific manner. We hypothesized that the differences seen in reproductive functions of males and females are associated with a sexually dimorphic gene expression profile of GnRH neurons. Methods and Results: We compared the transcriptome of GnRH neurons obtained from intact, metestrous female and male GnRH-GFP transgenic mice. About 1500 individual GnRH neurons from each sex were sampled with laser capture microdissection followed by whole transcriptome amplification for gene expression profiling. Under stringent selection criteria (fold change > 1.6, adjusted p-value 0.01), Affymetrix Mouse Genome 430 PM array analysis identified 543 differentially expressed genes. Sexual dimorphism was most apparent in gene clusters associated with synaptic communication, signal transduction, cell adhesion, vesicular transport and cell metabolism. To validate microarray results, 57 genes were selected and 91% of their differential expression was confirmed by real-time PCR. Similarly, 88% of microarray results were confirmed with PCR from independent samples obtained by patch pipette harvesting and pooling of 30 GnRH neurons from each sex. We found significant differences in expression of genes involved in vesicle priming and docking (Syt1, Cplx1), GABAergic (Gabra3, Gabrb3, Gabrg2) and glutamatergic (Gria1, Grin1, Slc17a6) neurotransmission, peptide signaling (Sstr3, Npr2, Cxcr4) and the regulation of intracellular ion homeostasis (Cacna1, Cacnb1, Cacng5, Kcnq2, Kcnc1). Conclusion: The striking sexual dimorphism of the GnRH neuron transcriptome we report here contributes to the better understanding the differences in cellular mechanisms of GnRH neurons in the two sexes.

2021-01-18 | GSE66806 | GEO