Genomic imprinting of the metabolic regulator gene Klf14 is regulated by a paternal sub-TAD anchored at Mest.

Maternally methylated Mest gDMR regulates Klf14 imprinting through allele-specific TAD restructuring in mice and humans.

• Why it matters: Understanding the mechanisms controlling genomic imprinting at the Klf14 locus is crucial because variants influence type 2 diabetes and metabolic syndrome risk, yet the regulatory processes remain unclear.
• What they did: The study used allele-specific 4C-seq, CRISPR-Cas9 deletions, and chromatin analysis to show that the unmethylated Mest gDMR creates a paternal sub-TAD that controls Klf14 expression, with a shared enhancer identified in pituitary cells.
• The result: Findings reveal that the Mest gDMR acts as an imprinting control region by modulating TAD structures, enabling long-range regulation of Klf14 imprinting, which advances understanding of epigenetic regulation in metabolic disease.