Broad domains of histone H3 lysine 4 trimethylation in transcriptional regulation and disease

Histone modifications affect transcription by changing the chromatin structure. In particular, histone H3 lysine 4 trimethylation (H3K4me3) is one of the most recognized epigenetic marks of active transcription. While many studies have provided evidence of the correlation between H3K4me3 and active transcription, details regarding the mechanism involved remain unclear. The first study on the broad H3K4me3 domain was reported in 2014; subsequently, the function of this domain has been studied in various cell types. In this review, we summarized the recent studies on the role of the broad H3K4me3 domain in transcription, development, memory formation, and several diseases, including cancer and autoimmune diseases. The broadest H3K4me3 domains are associated with increased transcriptional precision of cell-type-specific genes related to cell identity and other essential functions. The broad H3K4me3 domain regulates maternal zygotic activation in early mammalian development. In systemic autoimmune diseases, high expression of immune-responsive genes requires the presence of the broad H3K4me3 domain in the promoter-proximal regions. Transcriptional repression of tumor-suppressor genes is associated with the shortening of the broad H3K4me3 domains in cancer cells. Additionally, the broad H3K4me3 domain interacts with the super-enhancer to regulate cancer-associated genes. During memory formation, H3K4me3 breadth is regulated in the hippocampus CA1 neurons. Taken together, these findings indicate that H3K4me3 breadth is essential for the regulation of the transcriptional output across multiple cell types.