Histone H3 lysine 36 dimethylation (H3K36me2) plays a key role in transcriptional elongation and chromatin organization, yet how its deposition is spatially controlled across the genome remains unclear. Here, we identify TOP1 as a critical recruiter of the H3K36me2 methyltransferase NSD2 to gene bodies. Disruption of the TOP1–NSD2 interaction reduces H3K36me2 at gene bodies, impairs RNA polymerase II release, and represses transcription. Remarkably, loss of this recruitment increases H3K36me2 at repetitive sequences, licensing their aberrant transcriptional activation. We show that NSD2 is primarily responsible for depositing H3K36me2 at these loci. We further identify MTA1 as a recruiter of NSD2 to repetitive elements via recognition of the GATC consensus sequence. Together, TOP1 and MTA1 spatially partition NSD2 across the genome, enabling H3K36me2 to serve dual roles in regulating canonical gene expression and acting as an active mark for the transcriptional activation of repetitive sequences.
Triple-negative breast cancer (TNBC) is known for its aggressive nature, and TNBC management is currently challenging due to the lack of effective targets. Despite the importance of histone post-translational modifications (hPTMs) in breast cancer, their associations with molecular subtypes of breast cancer, especially TNBC, are poorly understood. In this study, a combination of untargeted and targeted proteomics approaches, supplemented by a derivatization method, was applied to breast cancer cells and tissue samples. Untargeted proteomics of eight breast cancer cell lines belonging to different molecular subtypes revealed 36 modified peptides with 12 lysine modification sites in histone H3, and the most frequently reported top 5 histone H3 methylation and acetylation sites were covered. Then, targeted proteomics was carried out to quantify the total 20 target hPTMs at the covered modification sites (i.e., mono-, di-, trimethylation, and acetylation for each site), indicating the difficulty in distinguishing TNBC cells from normal cells. Subsequently, the analysis in TNBC patients revealed significant expression differences in 4 specific hPTMs (H3K14ac, H3K27me1, H3K36me2, and H3K36me3) between TNBC and adjacent normal tissue samples. These unique hPTM patterns allowed for the differentiation of TNBC from normal cases. This finding provides promising implications for advancing targeted treatment strategies for TNBC in the future.
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