Ryan, D. H. | bioRxiv Science

bioRxiv2026

Maintenance DNA methylation is necessary for age-related alterations in regulatory T cell transcriptional and DNA methylation signatures

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, restrain immune responses during inflammatory stimuli, and promote tissue function and repair. Treg cell lineage identity, stability, and function depend on specific DNA methylation patterns maintained by the epigenetic regulator, UHRF1. Aging disrupts DNA methylation patterns necessary for Treg cell-mediated lung repair in a cell-autonomous manner. Nevertheless, whether maintenance DNA methylation is necessary for age-related Treg cell transcriptional and methylation programs is unknown. Here, we performed transcriptional and DNA methylation profiling on young and old Treg cells isolated from mice with chimeric Treg cell-specific loss of UHRF1. We observed cell-autonomous, age-related alterations in transcriptional and DNA methylation signatures that were dependent on UHRF1. We conclude that maintenance DNA methylation is required for age-related alterations in Treg cell transcriptional and DNA methylation signatures.

immunology↗

bioRxiv2026

A bivalent lysine-acetylated small-molecule binding site in MYC

MYC is an important, yet challenging target in oncology as it lacks traditional druggable pockets. Here, we show that two regions of MYC, the basic-helix-loop-helix (bHLH) domain, and extended MYC Box II (eMBII) come together to form a bivalent, high-affinity small-molecule MYC inhibitor (MYCi) binding site. CRISPR-tiling mutagenesis identified mutations in the vicinity of the eMBII and bHLH regions that together confer MYCi resistance. Importantly, acetylation of K148 in eMBII, which is essential for MYC oncogenicity in vivo, enhanced MYCi binding affinity and is predicted to increase the structural order of this region. Furthermore, MYCi selectively modulated the expression of the same genes regulated by lysine-acetylated MYC in cancer cells. These studies provide a rationale for selective targeting of acetylated, oncogenic MYC with small molecules.

cancer biology↗