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Regulatory connections of B cell signaling deciphered by CRISPR screens unveils mTOR and GSK3 as major immune response regulators

ABSTRACT: Dysregulated gene expression in germinal center (GC) B cells is associated with autoimmune disorders and lymphoma. To detect pivotal gene regulators and potential therapeutic targets, we fluorescently labeled 47 key B cell genes and performed genome-wide sgRNA screens in GC-lymphoma cells. We identified 4,440 regulators and 17,638 connections containing regulatory directions and strength. We developed the interactive data portal B-LEARN, to access, analyze and visualize the molecular network data. Mechanistic Target of Rapamycin (mTOR) signaling forms a regulator hub accounting for ~40% of regulators identified. Using reporter cell lines, we evaluated impact of rapamycin, a potent mTOR inhibitor, which repressed cell cycle genes early post-treatment but unexpectedly increased immune response genes later. Glycogen synthase kinase 3 (GSK3) counteracted mTOR for immune gene expression and cell cycle control but not translation. The matching set of reporter cell lines and interactive data portal will be a useful resource for future studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290879 | GEO | 2025/08/19

REPOSITORIES: GEO

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Project description:Mitochondrial oxidative function is tightly controlled to maintain energy homeostasis in response to nutrient and hormonal signals. An important cellular component in the energy sensing response is the target of rapamycin (TOR) kinase pathway; however whether and how mTOR controls mitochondrial oxidative activity is unknown. Here, we show that mTOR kinase activity stimulates mitochondrial gene expression and oxidative function. In skeletal muscle cells and TSC2-/- MEFs, the mTOR inhibitor rapamycin largely decreased gene expression of mitochondrial transcriptional regulators such as PGC-1alpha and the transcription factors ERRalpha and NRFs. As a consequence, mitochondrial gene expression and oxygen consumption were reduced upon mTOR inhibition. Using computational genomics, we identified the transcription factor YY1 as a common target of mTOR and PGC-1alpha that controls mitochondrial gene expression. Inhibition of mTOR resulted in a failure of YY1 to interact and be coactivated by PGC-1alpha. Notably, knock-down of YY1 in skeletal muscle cells caused a significant decrease in mRNAs of mitochondrial regulators and mitochondrial genes that resulted in a decrease in respiration. Moreover, YY1 was required for rapamycin-dependent repression of mitochondrial genes. Thus, we have identified a novel mechanism in which a nutrient sensor (mTOR) balances energy metabolism via transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer. Experiment Overall Design: Using Affymetrix MOE430 v2 gene chips, biological triplicates of each condition were analyzed: vehicle-treated, rapamycin-treated, gfp-infected, and pgc-1alpha-infected resulting in a total of 12 samples. Experiment Overall Design: Data were analyzed by RMA (with default settings) in BioConductor 1.2 -- one batch for the Rapamycin vs. Vehicle, and another batch for the PGC vs GFP.

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Regulatory connections of B cell signaling deciphered by CRISPR screens unveils mTOR and GSK3 as major immune response regulators

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