Transcription factor recognition models with modified nucleobases

点击翻译按钮获取中文摘要

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.