SFB 1309: Chemical Biology of Epigenetic Modifications

在细胞中通过DNA复制、RNA转录和蛋白质翻译产生的生物分子通常被化学修饰。DNA含有修饰的核苷，以增加遗传密码的多样性，这是在主动和被动之间转换遗传系统部分所必需的。RNA含有非规范核苷以引入信息编码以外的功能。需要这些修饰来微调解码过程并稳定特定的RNA折叠。反过来，蛋白质在合成后被修饰，以调节它们与其他蛋白质、核酸的相互作用，调节它们在细胞中的分布并搅拌它们的稳定性。所有生物分子上的化学语言建立了一个新的表观遗传信息层，它不是由DNA序列编码的。CRC 1309的首要目标是解码该信息层。我们的目标是调查和操纵的结构的修改层。在A区，我们正在研究DNA和RNA的修饰。在B区，蛋白质的修饰化学是重点。最后，在区域C中，CRC 1309开发新技术来研究该新信息层。开发了新的测序方法来破译修饰的核苷位于基因组或转录组中的位置。需要新的质谱工具来研究蛋白质和核酸修饰的内容和动力学。CRC 1309使用化学生物学技术来实现这些目标。修饰的核苷通过现代溶液相化学法化学合成。固相化学方法用于制备特异性修饰的DNA和RNA。这些化学工具与细胞生物学相结合，以了解体内修饰化学的功能。为了能够操纵表观遗传信息层，开发了用作进行修饰化学的酶的特异性抑制剂的分子。这些化合物为治疗疾病打开了新的大门。新的分析方法使我们能够研究生物圈中蛋白质和核苷中修饰氨基酸的分布。它们引领了新的癌症诊断工具的发展。利用现代细胞生物学，我们揭示了这些蛋白质和寡核苷酸的非经典构建模块如何允许更高的多细胞生物协调转录活性，特别是在细胞发育和神经元分化期间。最后，我们研究了改性化学是如何演变的。例如，非规范核苷是早期RNA世界的遗物，还是它们是晚期发展所需的，以使生命进入更高的复杂性水平？CRC 1309的首要目标是理解生物分子上的化学语言，并开发分子来操纵此信息层，以便为新的医疗干预可能性奠定基础。

Biomolecules that are produced in cells by DNA replication, RNA transcription and protein translation are often chemically modified. DNA contains modified nucleosides in order to increase the diversity of the genetic code, which is needed to switch parts of the genetic system between active and passive. RNA contains non-canonical nucleosides to introduce functions beyond information encoding. The modifications are needed to fine tune the decoding process and to stabilize specific RNA folds. Proteins in turn are post-synthetically modified in order to modulate their interaction with other proteins, with nucleic acids, to regulate their distribution in the cell and to stir their stability. The chemical language on all biomolecules establishes a new epigenetic layer of information that is not encoded by the DNA sequence. The CRC 1309 has the overarching goal to decode this information layer. Our aims are to investigate and manipulate the structure of the modification layers. In area A we are studying modifications on DNA and RNA. In area B the modification chemistry on proteins is in the focus. Finally, in area C the CRC 1309 develops new technologies to study this new information layer. New sequencing methods are developed to decipher, where modified nucleosides are situated in the genome or transcriptome. New mass spectrometry tools are required to investigate the content and dynamics of protein and nucleic acid modifications. The CRC 1309 uses the technologies of Chemical Biology to approach these goals. The modified nucleosides are chemically synthesized by modern solution phase chemistry. Solid phase chemistry methods are employed to prepare specifically modified DNA and RNA. These chemical tools are combined with Cell Biology to understand the function of the modification chemistry in vivo. In order to enable manipulation of the epigenetic information layer, molecules are developed that function as specific inhibitors for the enzymes that perform the modification chemistry. These compounds open new doors for the treatment of diseases. The new analytical methods allow us to study the distribution of modified amino acids in proteins and nucleosides in the biosphere. They lead the way to new cancer diagnostic tools. Using modern Cell Biology, we unravel how these non-canonical building blocks of proteins and oligonucleotides allow higher multicellular organisms to orchestrate transcriptional activity, particularly during cellular development and neuronal differentiation. Finally, we study how the modification chemistry evolved. Are for example non-canonical nucleosides relics of an early RNA world, or are they late developments that were needed to allow life to move to a higher level of complexity? The overarching goal of the CRC 1309 is to understand the chemical language on biomolecules and to develop molecules to manipulate this information layer in order set the ground for new medical intervention possibilities.