Transcription factor recognition models with modified nucleobases

转录因子驱动哺乳动物基因表达程序，通过在特定序列和表观基因组环境中结合DNA来启动转录。转录因子的序列特异性已经被广泛研究了几十年。表观基因组背景的研究直到后来才随着翻译后组蛋白修饰和DNA甲基化的大规模数据而成为可能。在甲基化DNA中，胞嘧啶（C）转化为修饰形式5-甲基胞嘧啶（5 mC）。DNA甲基化可以通过非序列特异性5 mC结合蛋白影响转录，这可以沉默基因。尽管如此，一些转录因子优先结合含有5 mC的特定序列，而不是未修饰的C，反之亦然。随着时间的推移，甚至在细胞分裂期间，细胞保持稳定的DNA甲基化状态。这意味着甲基化对转录因子结合的影响比其他更短暂的表观基因组标记更持久。除了5 mC，最近的研究揭示了其他三种胞嘧啶修饰的生物学重要性，5-羟甲基胞嘧啶（5 hmC），5-甲酰基胞嘧啶（5 fC）和5-羧基胞嘧啶（5caC）。其他研究表明，这些修饰也会影响转录因子对DNA的识别，就像5 mC一样。然而，没有工具来预测转录因子对考虑修饰的核碱基的存在或不存在的结合位点的亲和力。这阻碍了对胞嘧啶修饰对基因调控的影响的充分理解。

Transcription factors drive mammalian gene expression programs, initiating transcription by binding DNA in specific sequence and epigenomic contexts. Sequence specificity of transcription factors has been studied extensively for decades. The study of epigenomic contexts became possible only later with large-scale data on post-translational histone modifications and DNA methylation. In methylated DNA, cytosine (C) undergoes conversion to a modified form, 5-methylcytosine (5mC). DNA methylation can influence transcription through non-sequence-specific 5mC-binding proteins which can silence genes. Nonetheless, some transcription factors preferentially bind specific sequences containing 5mC rather than unmodified C, or vice versa. The cell maintains stable DNA methylation states over time and even across cell divisions. This means methylation can exhibit a more sustained impact on transcription factor binding than other, more transient, epigenomic marks. In addition to 5mC, recent studies reveal the biological importance of three other cytosine modifications, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Other studies show that these modifications also affect transcription factor recognition of DNA just as 5mC does. There are no tools, however, to predict transcription factor affinity for binding sites that consider the presence or absence of modified nucleobases. This prevents a full understanding of the impact of cytosine modifications on gene regulation.