SETD2 是唯一负责转录偶联组蛋白 H3 赖氨酸 36 三甲基化 (H3K36me3) 的酶。 SETD2 突变会导致人类疾病，包括癌症和发育缺陷。在小鼠中，Setd2 对于胚胎血管重塑至关重要。鉴于最近发现许多表观遗传修饰剂具有非催化功能，目前尚不清楚 Setd2 的主要功能是否依赖于其催化活性。在这里，我们建立了一个位点特异性敲入小鼠模型，其中含有癌症患者衍生的催化死亡 Setd2 (Setd2-CD)。我们发现 Setd2 在小鼠发育中的重要性取决于其甲基转移酶活性，因为 Setd2CD/CD 和 Setd2-/- 小鼠表现出相似的胚胎致死表型和很大程度上相似的基因表达模式。然而，与Setd2-/-相比，Setd2CD/CD小鼠的尿囊发育缺陷较轻，单细胞RNA-seq分析揭示了这两种模型中尿囊特异性5'Hoxa簇基因的差异调节。总的来说，这项研究阐明了 Setd2 催化活性在小鼠发育中的重要性，并为以前未识别的 Setd2 功能的比较研究提供了新模型。© 2024。高等教育出版社。

SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3). Mutations in SETD2 cause human diseases including cancer and developmental defects. In mice, Setd2 is essential for embryonic vascular remodeling. Given that many epigenetic modifiers have recently been found to possess noncatalytic functions, it is unknown whether the major function(s) of Setd2 is dependent on its catalytic activity or not. Here, we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2 (Setd2-CD). We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity, as the Setd2CD/CD and Setd2-/- mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns. However, compared with Setd2-/-, the Setd2CD/CD mice showed less severe defects in allantois development, and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5' Hoxa cluster genes in these two models. Collectively, this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.© 2024. Higher Education Press.