Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, La Tronche, France.
Nucleic Acids Res. 2018 May 18;46(9):4327-4343. doi: 10.1093/nar/gky240.
CARM1 is a protein arginine methyltransferase (PRMT) that has been firmly implicated in transcriptional regulation. However, the molecular mechanisms by which CARM1 orchestrates transcriptional regulation are not fully understood, especially in a tissue-specific context. We found that Carm1 is highly expressed in the mouse testis and localizes to the nucleus in spermatids, suggesting an important role for Carm1 in spermiogenesis. Using a germline-specific conditional Carm1 knockout mouse model, we found that it is essential for the late stages of haploid germ cell development. Loss of Carm1 led to a low sperm count and deformed sperm heads that can be attributed to defective elongation of round spermatids. RNA-seq analysis of Carm1-null spermatids revealed that the deregulated genes fell into similar categories as those impacted by p300-loss, thus providing a link between Carm1 and p300. Importantly, p300 has long been known to be a major Carm1 substrate. We found that CREMτ, a key testis-specific transcription factor, associates with p300 through its activator, ACT, and that this interaction is negatively regulated by the methylation of p300 by Carm1. Thus, high nuclear Carm1 levels negatively impact the p300•ACT•CREMτ axis during late stages of spermiogenesis.
CARM1 是一种精氨酸甲基转移酶（PRMT），它已被明确牵涉到转录调控中。然而，CARM1 协调转录调控的分子机制尚未完全了解，尤其是在组织特异性的背景下。我们发现 Carm1 在小鼠睾丸中高度表达，并在精细胞中定位于核内，这表明 Carm1 在精子发生中具有重要作用。使用生殖系特异性条件性 Carm1 敲除小鼠模型，我们发现 Carm1 对于单倍体生殖细胞发育的晚期阶段是必需的。Carm1 的缺失导致精子数量减少和精子头部变形，这可归因于圆形精细胞伸长的缺陷。对 Carm1 缺失的精细胞进行 RNA-seq 分析表明，失调的基因属于与 p300 缺失影响的相似类别，从而在 Carm1 和 p300 之间建立了联系。重要的是，p300 长期以来一直被认为是 Carm1 的主要底物。我们发现，Cremτ，一种关键的睾丸特异性转录因子，通过其激活因子 ACT 与 p300 相关联，而这种相互作用受到 Carm1 对 p300 的甲基化的负调控。因此，在精子发生的晚期阶段，高核 Carm1 水平会对 p300•ACT•Cremτ 轴产生负面影响。
