Gene regulatory basis of bystander activation in CD8+ T cells (ATAC-seq)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE180731 | GEO | 2024/02/26
REPOSITORIES: GEO
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Project description:The immune system is stratified into layers of specialized cells with distinct functions. Recently, Lin28b was shown to serve as a master regulator of fetal lymphopoiesis and program the development of more innate-like lymphocytes in early life. However, it is still unclear how Lin28b alters the function of fetal-derived lymphocytes and protects the host against infection. In this report, we examined how Lin28b transcriptionally and epigenetically programs murine CD8+ T cells for innate immune defense and translated our key findings to human CD8+ T cells. We found that Lin28b operates as a gatekeeper, opening the door to a hidden diversity of phenotypes that are unveiled upon stimulation with innate cytokines. In particular, Lin28b promotes a transcriptionally and functionally diverse pool of cells through chromatin remodeling. As a result, neonatal CD8+ T cells are able to deploy a bet-hedging immune strategy and protect the host against a wide range of unrelated pathogens.
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Project description:The RNA binding protein Lin28b is highly expressed during embryogenesis but its expression declines in adult tissues, and aberrant expression of Lin28b is associated with tumour development and maintenance. Lin28b regulates the translation of several glycolytic and mitochondrial enzymes in order to enhance cellular metabolism and energy production. Lin28b is repressed by let-7 family microRNAs in a reciprocal negative regulatory circuitry where Lin28b supresses maturation of let-7. This circuitry obtains input from master regulators such as MYC that transcriptionally upregulates Lin28b, which is required for let-7 suppression and proliferation. Not much is known of how this circuitry is regulated through transcription of the let-7 microRNAs. Here we show that the transcription factor C/EBPβ-LIP induces aerobic glycolysis and mitochondrial respiration reminiscent to cancer cell metabolism. By integrating transcriptome, proteome and metabolic flux analysis we reveal that this LIP-induced metabolic reprogramming is dependent on Lin28b and that LIP enhances Lin28b expression through transcriptional repression of the let-7 microRNA family. Transgenic mice overexpressing LIP have reduced levels of let-7 in bone marrow, skin and spleen, which is associated with induction of Lin28b and hyperplasia. This study establishes LIP as a regulator of the let-7/Lin28b regulatory circuitry and we hypothesize that the LIP-controlled let-7/Lin28b regulation is involved in the de-regulation of tissue homeostasis and tumourigenesis.
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