iScience. 2026 Jul 25;29(8):116915. doi: 10.1016/j.isci.2026.116915. eCollection 2026 Aug 21.
ABSTRACT
Cryptic transcription is an aberrant form of transcription that initiates from non-canonical, non-promoter regions within the gene. In mammals, a repressive chromatin state effectively inhibits cryptic transcription, preserving transcriptional fidelity. Aging-induced loss of trimethylated lysine 36 on histone H3 reduces DNA methylation, and accumulation of promoter-like histone modifications renders gene bodies permissive to spurious initiation by RNA polymerase II. This allows previously repressed intragenic regions to acquire promoter-like chromatin features. Cryptic transcription produces aberrant RNAs that interfere with normal gene expression, leading to truncated proteins or nonfunctional mRNAs. The aberrant RNA and protein products impair stem cell self-renewal and differentiation, thereby contributing to the development of aging and disease. This review summarizes the mechanisms underlying age-related cryptic transcription, focusing on the function of H3K36me3, DNA methylation, H3K4me3, H3K27ac, and transcription factors. In addition, we discuss the effects of cryptic transcription on aging stem cells and aged tissues.
PMID:42564700 | PMC:PMC13444477 | DOI:10.1016/j.isci.2026.116915
