Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Neuronal expression of bromodomain proteins alter neuronal health and peripheral protein homeostasis to promote longevity

ABSTRACT: Longevity and stress resilience require coordinated gene expression across tissues. We found that neuronal overexpression of the chromatin reader BET-1 in C. elegans extends lifespan and enhances stress resistance through cell non-autonomous signaling. Neuronal BET-1 triggers a neurotransmitter-dependent activation of the conserved transcription factor HSF-1 in the intestine, promoting proteostasis, oxidative stress resistance, and immune defense. To uncover the molecular mechanisms underlying this systemic response, we performed bulk RNA sequencing, which revealed coordinated activation of gene networks involved in heat-shock response, proteostasis, and pathogen resistance. These transcriptomic signatures define the downstream effectors of neuronal BET-1 and highlight distinct regulatory mechanisms mediated by hsf-1 and daf-16. Together, these findings establish BET-1 as a key regulator of inter-tissue communication and demonstrate the critical role of RNA-seq in identifying the transcriptional programs that couple neuronal signaling to organismal longevity and resilience.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Caenorhabditis elegans

SUBMITTER: Ryo Higuchi-Sanabria

PROVIDER: E-MTAB-15906 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that gene mutations that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons enhance survival during hypertonic stress. Enhanced survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, loss of ASH neuron function reduces protein damage in non-neuronal cells. Improved proteostasis capacity is due in part to upregulation of genes that play important roles in managing protein damage. We propose that inhibitory signaling from ASH neurons normally suppresses expression of genes required for non-neuronal cell proteostasis. Because all cells have the capacity to sense and respond to stressors, inhibitory neuronal signaling may be important for minimizing activation of cellular stress resistance and proteostasis pathways during short duration and less extreme stressors or stressors that can be avoided by behavioral changes. Neuronal regulation of systemic proteostasis allows the nervous system to monitor environmental variables and more effectively partition finite energy resources between different organismal processes. Our studies add to a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. mRNA expression profiling of synchronized L4 stage wild-type N2 Bristol and VC1262 osm-9(ok1677) C. elegans strains under control (51mM NaCl) and hypertonic stress (200mM NaCl).

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Neuronal expression of bromodomain proteins alter neuronal health and peripheral protein homeostasis to promote longevity

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