核形状的维持对于细胞稳态至关重要，这一过程的破坏与各种病理状况有关，包括癌症、核纤层蛋白病和衰老。尽管核形状很重要，但控制它的精确分子机制尚未完全了解。在这项研究中，我们确定了包含 YEATS 结构域的蛋白 4 (GAS41) 是一种先前未识别的参与调节核形态的因子。结直肠癌细胞中 GAS41 的基因消除导致核形状显着异常，并在体外和体内抑制癌细胞增殖。恢复实验表明，野生型 GAS41，而非缺乏组蛋白 H3 赖氨酸 27 乙酰化或巴豆酰化 (H3K27ac/cr) 结合的 YEATS 结构域突变体，挽救了 GAS41 缺陷细胞中的异常核表型，这凸显了 GAS41 与 H3K27ac 结合的重要性/cr 参与核形状调节。进一步的实验表明，GAS41 与 H3K27ac/cr 相互作用，调节关键核形状调节因子的表达，包括 LMNB1、LMNB2、SYNE4 和 LEMD2。从机制上讲，GAS41 将 BRD2 和介导复合物招募到这些调节因子的基因位点，促进它们的转录激活。 GAS41-H3K27ac/cr 结合的破坏导致 BRD2、MED14 和 MED23 从基因位点解离，导致核形状异常。总体而言，我们的研究结果表明，GAS41 与 BRD2 和介导复合体合作来控制关键核形状调节因子的表达。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The maintenance of nuclear shape is essential for cellular homeostasis and disruptions in this process have been linked to various pathological conditions, including cancer, laminopathies, and aging. Despite the significance of nuclear shape, the precise molecular mechanisms controlling it are not fully understood. In this study, we have identified the YEATS domain-containing protein 4 (GAS41) as a previously unidentified factor involved in regulating nuclear morphology. Genetic ablation of GAS41 in colorectal cancer cells resulted in significant abnormalities in nuclear shape and inhibited cancer cell proliferation both in vitro and in vivo. Restoration experiments revealed that wild-type GAS41, but not a YEATS domain mutant devoid of histone H3 lysine 27 acetylation or crotonylation (H3K27ac/cr) binding, rescued the aberrant nuclear phenotypes in GAS41-deficient cells, highlighting the importance of GAS41's binding to H3K27ac/cr in nuclear shape regulation. Further experiments showed that GAS41 interacts with H3K27ac/cr to regulate the expression of key nuclear shape regulators, including LMNB1, LMNB2, SYNE4, and LEMD2. Mechanistically, GAS41 recruited BRD2 and the Mediator complex to gene loci of these regulators, promoting their transcriptional activation. Disruption of GAS41-H3K27ac/cr binding caused BRD2, MED14 and MED23 to dissociate from gene loci, leading to nuclear shape abnormalities. Overall, our findings demonstrate that GAS41 collaborates with BRD2 and the Mediator complex to control the expression of crucial nuclear shape regulators.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.