Recent studies are elucidating molecular underpinnings of complex diseases. Research on SETD1B epigenetic regulation reveals its role in aggressive acute myeloid leukemia with FLT3-ITD mutation. A prime editing screen uncovered functional synonymous mutations affecting human cell fitness, revising assumptions of genetic silent sites. Additionally, TET1 enzyme has been highlighted for its contrasting roles in cancer progression and neurological disorders through DNA demethylation. These insights advance the mechanistic comprehension and potential therapeutic targeting of genetic and epigenetic alterations across diseases.