YEATS4 Reads Histone Crotonylation to Promote Fatty Acid Metabolism and Cancer Cell Stemness [CUT&Tag]

How histone lysine crotonylation (Kcr) is read and interpreted remains to be elucidated. We report here that YEATS4, a potential breast cancer driver identified recently by two independent genome-wide association studies, is a reader of H3K14cr. Integrative metabolomic, epigenomic, and transcriptomic analyses reveal that H3K14cr reading by YEATS4 is associated with a shift of cellular metabolic profile and transcription activation of a cohort of genes, including CD36, CPT1A, and ACOX1, that are critically involved in the uptake and metabolism of fatty acids. High expression of YEATS4 fortifies fatty acid metabolism, enhances self-renewal and growth of ALDH+ breast cancer stem cells, and is correlated with poor prognosis of breast cancer patients, especially the ER+ subtype. Our work uncovers YEATS4 as an “amplifier” in the feedforward circuit of histone crotonylation and lipid metabolism underlying the stemness and cell proliferation, supporting the pursuit of YEATS4 as a potential target for breast cancer intervention. Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing for YEATS domain family protein YEATS4 and histone modifications H3K14cr and H3K27ac in MCF-7 cells.