Dear Editor,

Histone lysine methylations are essential components of the epigenetic regulatory mechanisms. Although major histone lysine methylations have been extensively investigated, low-abundance methylations remain largely elusive. Among the low-abundance methylations, H3K14me3 has been identified in mammalian cells upon pathological infection by Legionella pneumophila, a gram-negative bacterium and causative agent of a severe form of pneumonia. Global host chromatin H3K14 trimethylation and transcription repression are mediated by an H3K14 methyltransferase, regulator of methylation A (RomA) encoded by the bacterial genome.1 Importantly, previous mass spectrometry studies also suggested the presence of endogenous H3K14 methylations among eukaryotes,2,3,4,5,6,7 although these findings have not been confirmed by independent means. In addition, the genomic distribution as well as the H3K14me3 regulatory enzymes have not been identified. Here, using an H3K14me3-specific antiserum we report the identification of distinct and shared H3K14me3 distribution patterns in HEK293T and human embryonic stem cells (hESCs), two cell lines with extensive epigenome profiles allowing cross comparisons with other known histone marks. H3K14me3 heavily decorates the KRAB-ZNF (Krupple-associated box containing zinc finger gene) clusters in both HEK293T and hESC cells but is only strongly associated with active transcription in HEK293T cells, where it binds thousands of active promoters. We further profiled H3K14me3 in a mouse melanoma cell line, B16, and discovered similar distribution features to those in HEK293T cells. Importantly, we identified members of the KDM4 family of histone demethylases (KDM4A, KDM4B and KDM4C) as H3K14me3 demethylases. As the KDM4 family members have been shown to mediate H3K9me3 and H3K36me3 demethylation,8 our findings also revealed crosstalks among these modifications.

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