Molecular mechanisms and cellular functions of the CpG island-binding protein SAMD1

精确的基因表达对于体内细胞的正常运作至关重要。我们最近发现SAM结构域包含蛋白1(SAMD1)是一种独特的转录调节因子，作用于未甲基化的CpG岛。SAMD1具有一个CpG岛结合域和一个多聚体SAM结构域。它与几种染色质调节蛋白相互作用，包括组蛋白去甲基酶KDM1A和染色质调节因子L3MBTL3。我们的工作表明，SAMD1主要作为转录抑制因子发挥作用，它的缺失会导致基因调控过程的异常。SAMD1在所有组织中都有表达，暗示着丰富的生物学功能，这是由缺乏SAMD1的小鼠的胚胎致死性支持的。虽然我们对SAMD1的初步描述已经提供了一些有趣的见解，但SAMD1的S功能的许多方面仍有待探索。在我们的研究中，我们的目标是表征SAMD1的分子机制和细胞功能。在本研究方案中，我们的目标是1)阐明SAMD1染色质结合的机制，2)研究SAMD1‘S抑制活性的分子过程，3)评估SAMD1的S多聚体能力在染色质远程相互作用中的潜在作用，4)研究SAMD1在神经元分化过程中的作用。我们期待从这项工作中获得关于这种独特的染色质调节因子的分子和细胞功能的新见解，这将有助于理解它在基因调控过程中的功能以及它的失调可能如何导致人类疾病。

Precise gene expression is essential for the proper functioning of cells in the body. We recently identified SAM domain-containing protein 1 (SAMD1) as a unique transcriptional regulator that acts at unmethylated CpG islands. SAMD1 is characterized by a CpG island-binding domain and a multimerizing SAM domain. It interacts with several chromatin regulatory proteins, including the histone demethylase KDM1A and the chromatin regulator L3MBTL3. Our work demonstrated that SAMD1 mainly functions as a transcriptional repressor and that its deletion leads to aberrant gene regulatory processes. SAMD1 is expressed in all tissues, implicating an abundant biological function, which is supported by embryonic lethality of mice that lack SAMD1. Although our initial characterization of SAMD1 already provided several fascinating insights, many aspects of SAMD1’s function remain to be explored. In our research, it is our goal to characterize the molecular mechanisms and cellular functions of SAMD1. In this research proposal, we aim 1) to elucidate the mechanisms that drive SAMD1 chromatin association, 2) to investigate the molecular process facilitated upon SAMD1’s repressive activity, 3) to assess the potential role of SAMD1’s multimerization ability in long-range chromatin interaction and 4) to investigate the role of SAMD1 during neuronal differentiation processes. We expect from this work novel insights about the molecular and cellular functions of this unique chromatin regulator, which will help to understand its function during gene regulatory processes and how its dysregulation may lead to human diseases.