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.

中文翻译：

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化学水合组蛋白H4通过LSD1–CoREST复合物刺激核内体去甲基化

赖氨酸特异性脱甲基酶1（LSD1）通过使组蛋白H3中的单和二甲基化的Lys4脱甲基化来下调真核基因的活性。阐明具有组蛋白翻译后修饰（PTM）的LSD1的生化串扰对于开发以LSD1为靶标的人类癌症疗法至关重要。我们用包含位点特异性甲基化和磺酰化组蛋白的半合成核小体询问了小泛素样修饰物（SUMO）驱动的LSD1活性调节。我们发现，包含与基因阻抑相关的修饰的磺酰化组蛋白H4（suH4）的核小体通过依赖于CoREST中SUMO相互作用基序的机制刺激LSD1活性。此外，suH4的刺激作用在空间上受到限制，并没有扩展到相邻的非磺酰化核小体的去甲基化。因此，