Dataset Information

Diminished transcriptional activity and splicing changes drive gene length-biased rewiring in the aging transcriptome (ChIP-seq)

ABSTRACT: Transcription by RNA polymerase II (RNAPII), which is essential for protein-coding gene expression and cellular function, is increasingly understood to become dysregulated with aging. Here, we use a multi-modal approach to comprehensively characterize age-dependent changes in RNAPII-mediated transcription in both mouse and human tissues. Short-read total RNA sequencing (RNA-seq) to profile nascent transcription reveals a global reduction in overall transcriptional activity/frequency in aged tissues, without apparent change in elongation rates. Transcriptomic analysis reveals a shift toward preferential expression of short genes in aged tissues, with notable upregulation of short stress-response genes and downregulation of long neurodevelopmental genes in the aged mouse brain. These results are recapitulated by analysis of total RNA-seq data from human tissues. Leveraging long-read RNA-seq, we determine that the representation of aberrant mono-exonic and intron-retention splice isoforms is increased in the aged mouse brain. Finally, we characterize the composition of RNAPII transcriptional machinery, finding that interactions between RNAPII and the Mediator complex are decreased in the chromatin of aged mouse liver and brain. Collectively, these analyses provide insight for future aging studies and reveal potential transcriptional control targets for anti-aging drug development.

ORGANISM(S): Mus musculus

PROVIDER: GSE282010 | GEO | 2026/05/31

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted of additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes—CAPG, LGALS3BP, NRIP1, and P2RY12—were found to share regulatory patterns in response to both aging and extrinsic activation. In-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.

Dataset Information

Diminished transcriptional activity and splicing changes drive gene length-biased rewiring in the aging transcriptome (ChIP-seq)

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets