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Genome-wide analysis of protein-DNA interactions

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Understanding the information encoded in the human genome requires two genetic codes, the first code specifies how mRNA sequence is converted to protein sequence, and the second code determines where and when the mRNAs are expressed. Although the proteins that read the second, regulatory code – transcription factors (TFs) – have been largely identified, the code is poorly understood as it is not known which sequences TFs can bind in the genome. To understand the regulatory code, we have analyzed the sequence-specific binding of TFs to unmodified and epigenetically modified DNA in the presence and absence of nucleosomes, using multiple different methods. Our findings indicate that DNA commonly mediates interactions between TFs, and that dimer formation results in changes in the binding preferences of TFs. We also found that CpG methylation has a major impact on TF binding. Binding of most major classes of TFs, including bHLH, bZIP, and ETS is inhibited by mCpG. In contrast, TFs that prefer to bind to methylated DNA mainly represent homeodomain, POU and NFAT proteins, and are enriched in TFs with central roles in embryonic and organismal development. Despite the extensive knowledge of TF binding preferences, reading the regulatory code remains a challenge. To address this, we have begun to identify the sources of this problem by performing several experiments that bridge the gap between in vivo analyses such as ChIP-seq and in vitro studies such as HT-SELEX. A binding model that is required to understand binding of TFs to the genome, which incorporates information about cellular TF activity, protein-protein interactions induced by DNA , and inheritance of epigenetic states across cell division will be discussed.

This talk is part of the Seminars at the Department of Biochemistry series.

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