CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells
CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells
复制标题
DOI：
10.1242/dev.037150
复制
发表时间：
2010-07-01
期刊：
影响因子：
4.6
通讯作者：
Kobayashi, Susumu
中科院分区：
文献类型：
--
作者：
O'Brien, Karen B.;Alberich-Jorda, Meritxell;Kobayashi, Susumu
共激活因子相关精氨酸甲基转移酶I （CARM1; PRMT4）通过多种机制调节基因表达，包括组蛋白甲基化和类固醇受体转录的共激活。缺乏CARM1的小鼠体型小，无法呼吸，出生后不久就会死亡，这表明CARM1在发育中起着至关重要的作用。在成人中，CARM1在人类iii级乳腺肿瘤和前列腺腺癌中过表达，并且CARM1的敲低抑制乳腺癌和前列腺癌细胞系的增殖。基于这些观察，我们假设小鼠胚胎中CARM1的缺失会抑制肺细胞增殖，导致呼吸窘迫。相比之下，我们在这里报告了CARM1的缺失导致胚胎发育期间肺上皮细胞的过度增殖。与野生型小鼠相比，缺乏CARM1的新生小鼠的肺部空间大大减少。在CARM1缺失的情况下，肺泡II型细胞增殖增加。电镜分析表明，缺乏CARM1的小鼠肺具有未成熟的肺泡II型细胞和肺泡I型细胞的缺失。基因表达分析揭示了细胞周期基因和分化标记在Carm1基因敲除肺中的失调。此外，在Carm1基因敲除和糖皮质激素受体敲除肺中存在基因表达重叠，这表明肺泡细胞的过度增殖和不成熟至少部分是由糖皮质激素介导的信号衰减引起的。这些结果首次证明CARM1抑制肺细胞增殖，并且是肺泡细胞正常分化所必需的。
Coactivator-associated arginine methyltransferase I (CARM1; PRMT4) regulates gene expression by multiple mechanisms including methylation of histones and coactivation of steroid receptor transcription. Mice lacking CARM1 are small, fail to breathe and die shortly after birth, demonstrating the crucial role of CARM1 in development. In adults, CARM1 is overexpressed in human grade-III breast tumors and prostate adenocarcinomas, and knockdown of CARM1 inhibits proliferation of breast and prostate cancer cell lines. Based on these observations, we hypothesized that loss of CARM1 in mouse embryos would inhibit pulmonary cell proliferation, resulting in respiratory distress. By contrast, we report here that loss of CARM1 results in hyperproliferation of pulmonary epithelial cells during embryonic development. The lungs of newborn mice lacking CARM1 have substantially reduced airspace compared with their wild-type littermates. In the absence of CARM1, alveolar type II cells show increased proliferation. Electron microscopic analyses demonstrate that lungs from mice lacking CARM1 have immature alveolar type II cells and an absence of alveolar type I cells. Gene expression analysis reveals a dysregulation of cell cycle genes and markers of differentiation in the Carm1 knockout lung. Furthermore, there is an overlap in gene expression in the Carm1 knockout and the glucocorticoid receptor knockout lung, suggesting that hyperproliferation and lack of maturation of the alveolar cells are at least in part caused by attenuation of glucocorticoid-mediated signaling. These results demonstrate for the first time that CARM1 inhibits pulmonary cell proliferation and is required for proper differentiation of alveolar cells.