The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.
Cell Metab
; 36(8): 1858-1881.e23, 2024 Aug 06.
Article
en En
| MEDLINE
| ID: mdl-38959897
ABSTRACT
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Envejecimiento
/
Cromatina
/
Factor de Transcripción AP-1
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2024
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
Estados Unidos