Chemically Sumoylated Histone H4 Stimulates Intranucleosomal Demethylation by the LSD1-CoREST Complex

Lysine-specific demethylase 1 (LSD1) downregulates eukaryotic gene activity by demethylating mono- and dimethylated Lys4 in histone H3. Elucidating the biochemical crosstalk of LSD1 with histone post-translational modifications (PTMs) is essential for developing LSD1-targeted therapeutics in human cancers. We interrogated the small ubiquitin-like modifier (SUMO)-driven regulation of LSD1 activity with semisynthetic nucleosomes containing site-specifically methylated and sumoylated histones. We discovered that nucleosomes containing sumoylated histone H4 (suH4), a modification associated with gene repression, stimulate LSD1 activity by a mechanism dependent upon the SUMO-interaction motif in CoREST. Furthermore, the stimulatory effect of suH4 was spatially limited and did not extend to the demethylation of adjacent nonsumoylated nucleosomes. Thus, we have identified histone modification by SUMO as the first PTM that stimulates intranucleosomal demethylation by the developmentally critical LSD1-CoREST complex.