KMT2B facilitates long-range gene regulation through LINE1 elements

Transcriptional regulation is tightly linked to chromatin organization, with H3K4me3 marking active and bivalent promoters. In embryonic stem cells, KMT2B deposits H3K4me3 at bivalent promoters, yet loss of H3K4me3 at these sites leaves developmental gene transcription largely unaltered. Here, we show that, in both mouse embryonic stem cells and during differentiation, the primary role of KMT2B is not to counteract Polycomb-mediated repression at bivalent promoters. Instead, we uncover a distinct regulatory function for KMT2B at the CG-rich 5’UTR of young LINE-1 elements. KMT2B binds LINE-1 5’UTRs and maintains their active chromatin state (H3K4me3, H3K27ac, H4K16ac) while preventing repressive H3K9me3 accumulation. Using complementary genomic methods and targeted deletions, we show that KMT2B-bound LINE-1 elements act as enhancers modulating neighboring gene expression in embryonic stem cells and, particularly, during differentiation. Our findings define KMT2B regulatory functions at LINE-1 repeats and highlight transposable elements as key components of long-range gene expression control. The authors demonstrate that KMT2B primarily regulates gene expression through LINE-1 elements with enhancer-like function, rather than by counteracting Polycomb repression, revealing an underappreciated link between Trithorax proteins and transposable elements during cell differentiation.