Hepatic Mettl14 Knockout Disrupts Bile Acid Homeostasis and Alters Fecal Microbiota Composition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1246563 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32983883_1.fastq.gz | Fastqsanger.gz | |||
| SRR32983883_2.fastq.gz | Fastqsanger.gz | |||
| SRR32983884_1.fastq.gz | Fastqsanger.gz | |||
| SRR32983884_2.fastq.gz | Fastqsanger.gz | |||
| SRR32983885_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause Microvillus Inclusion Disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b’s role in the intestine is well characterized, its function in the liver remains unclear. Methods & Results: To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNA-seq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. Conclusions: These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
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Project description:m6A regulates virtually every step in RNA metabolism. However, its toles in limb development remains largely unknown. To understand the roles, we created a limb bud-specific conditional knockout (cKO) mice and control heterozygous (cHet) mice of the Mettl14 gene, which encodes an essential subunit in the m6A methyltransferase complex METTL3/METTL14. We harvested limb buds from the mice on E12.5 and applied the proteins to quantitative mass spectrometry to understand how the depletion of Mettl14 affected the proteomes.
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Project description:RNA N6-methyladenosine (m6A) modification emerges as a pivotal mechanism underpinning numerous intracellular processes. METTL14 dimerizes with METTL3 as a m6A writer to install m6A on mRNA. Subsequently, m6A readers bind to m6A-marked RNAs to influence their metabolism/fate. However, there is a knowledge gap in m6A writers and readers governing liver metabolism. Glucose-6-phosphatase catalytic subunit (G6pc) is the gatekeeper of glycogenolysis and gluconeogenesis, determining hepatic glucose production (HGP); however, posttranscriptional regulation of G6pc is poorly understood. Here, we identify METTL14 as a posttranscriptional regulator of G6pc synthesis. Deletion of Mettl14 decreased, whereas overexpression of METTL14 increased, G6pc mRNA m6A methylation in hepatocytes. We mapped five m6A sites, and mutating the 5 sites (G6pcΔ5A) blocked METTL14-induced m6A methylation of G6pcΔ5A mRNA. METTL14 increased G6pc but not G6pcΔ5A mRNA stability and translation. YTHDF1 and YTHDF3 acted as m6A readers for G6pc mRNA to increase G6pc synthesis. Deletion of Mettl14 decreased gluconeogenesis in primary hepatocytes, liver slices, and mice. Liver METTL14, METTL3, and m6A-methylated G6pc mRNA were upregulated in mice with diet-induced obesity. Deletion of hepatic Mettl14 decreased HGP and mitigated diet-induced metabolic disorders. Collectively, these results unveil a previously-unrecognized METTL14/G6pc mRNA m6A/G6pc biosynthesis/HGP axis guiding glucose metabolism in health and disease.
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Project description:Spermatogenesis is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine (m6A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactiva- tion of the m6A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Com- bined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The sper- matids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermio- genesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.
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