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RNA Sequencing Analysis of MC38 tumors with Glutamate decarboxylase 1 Knockdown

ABSTRACT: Various types of cancers, including colorectal cancer, have shown an unusual dependence on glutamine. Glutamine can undergo an alternate fate in neurons: conversion into a non-proteinogenic amino acid gamma-aminobutyric acid (GABA) by the glutamic acid decarboxylase (GAD), including two family members GAD1 and GAD2. Some studies have shown that GAD1 expression is dysregulated in certain cancer types, but the effect of GAD1 on the tumorigenic process remain largely unknown. Thus, we use mouse colon adenocarcinoma MC38 tumor samples to perform RNA-sequencing (RNA-seq) assay. The goal of this study is to investigate GAD1-mediated transcriptome changes within tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE165889 | GEO | 2021/02/02

REPOSITORIES: GEO

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Project description:Background: Of the many neurotransmitters in humans, gamma-aminobutyric acid (GABA) shows potential for improving several mental health indications such as stress and anxiety. The microbiota-gut-brain axis is an important pathway for GABAergic effects, as microbially-secreted GABA within the gut can affect host mental functionhealth outcomes. Understanding the molecular characteristics of GABA production by microbes within the gut can offer insight to novel therapies for mental health. Results: Three strains of Levilactobacillus brevis with syntenous glutamate decarboxylase (GAD) operons were evaluated for overall growth, glutamate utilization, and GABA production in typical synthetic growth media supplemented with monosodium glutamate (MSG). Levilactobacillus brevis Lbr-6108 (Lbr-6108) and Levilactobacillus brevis Lbr-35 (Lbr-35) had similar growth profiles but differed significantly in GABA secretion and acid resistance. Lbr-6108 produced GABA early, within the growth phase, and produced significantly more GABA than Lbr-35 and the type strain Levilactobacillus brevis ATCC 14689 after the stationary phase. The global gene expression during GABA production was determined by RNA sequencing at several timepoints. The GAD operon, responsible for GABA production and secretion, activated in Lbr-6108 after only six hours of fermentation and continued throughout the stationary phase. Furthermore, Lbr-6108 activated many different acid resistance mechanisms concurrently, which contribute to acid tolerance and energy production. In contrast, Lbr-35, which has a genetically similar GAD operon, including two copies of the GAD gene, showed no upregulation of the GAD operon, even when cultured with MSG. Conclusions: This study is the first to evaluate whole transcriptome changes in L. brevis during GABA production over multiple timepoints. The concurrent expression of multiple acid-resistance mechanisms reveals niche-specific metabolic functionality between common human commensals and highlights the complex regulation of GABA metabolism in this important microbial species. Furthermore, the increased and rapid GABA production of Lbr-6108 highlights the strain’s potential as a therapeutic and the overall value of screening microbes for effector molecule output.

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RNA Sequencing Analysis of MC38 tumors with Glutamate decarboxylase 1 Knockdown

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