Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.

中文翻译：

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神经发育障碍和癌症中 BRPF1-KAT6 复合物导致的组蛋白 H3 丙酰化缺陷。


赖氨酸乙酰转移酶 6A (KAT6A) 及其旁系同源物 KAT6B 与含溴结构域和 PHD 指蛋白 1 (BRPF1) 形成化学计量复合物，用于乙酰化组蛋白 H3 的赖氨酸 23 (H3K23)。我们报告这些复合物还在体外和体内催化 H3K23 丙酰化。免疫荧光显微镜和 ATAC-See 揭示了这种修饰与活性染色质的关联。 Brpf1 缺失消除了小鼠胚胎和成纤维细胞中的酰化。此外，我们在 12 个先前未识别的综合征性智力障碍病例中发现了 BRPF1 变异，并证明这些病例和已知的 BRPF1 变异会损害 H3K23 丙酰化。一部分病例存在心脏异常。 H3K23 酰化也会受到癌症衍生的体细胞 BRPF1 突变的损害。丙戊酸盐、伏立诺他、丙酸盐和丁酸盐促进 H3K23 酰化。这些结果揭示了 BRPF1-KAT6 复合物的双重功能，揭示了相关发育障碍和各种癌症的潜在机制，并建议针对组蛋白酰化缺陷的疾病进行基于突变的治疗。