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

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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.