Integrative modeling of Transcription Factor cooperativity and its effects on phenotypic variability

The regulation of biological processes relies on a complex nucleotide code embedded in our DNA. Its decoding and interpretation is the main task of Transcription Factors (TFs), which altogether enable the recognition and modulation of gene expression. Whenever factors bind to DNA, a set of additional criteria and conditions need to be satisfied, such as TF concentration, DNA openness, and cooperativity with other binding factors. Such combinations of DNA-bound TFs, as well as their structural and functional cooperativity, allow a more fine-grained control of gene expression due to subtle changes in specificity in both DNA recognition and functional outcomes. This thesis explores the prediction of structural TF cooperativity and its biological consequences. Additionally, examples of functional cooperativity are presented and discussed in the context of neuronal activity and reprogramming. Altogether, this dissertation provides an extensive set of insights to better understand the complex interplay between TFs cooperativity and phenotypes

coTRaCTE predicts co-occurring transcription factors within cell-type specific enhancers

Cell-type specific gene expression is regulated by the combinatorial action of transcription factors (TFs). In this study, we predict transcription factor (TF) combinations that cooperatively bind in a cell-type specific manner. We first divide DNase hypersensitive sites into cell-type specifically open vs. ubiquitously open sites in 64 cell types to describe possible cell-type specific enhancers. Based on the pattern contrast between these two groups of sequences we develop "co-occurring TF predictor on Cell-Type specific Enhancers" (coTRaCTE) - a novel statistical method to determine regulatory TF co-occurrences. Contrasting the co-binding of TF pairs between cell-type specific and ubiquitously open chromatin guarantees the high cell-type specificity of the predictions. coTRaCTE predicts more than 2000 co-occurring TF pairs in 64 cell types. The large majority (70%) of these TF pairs is highly cell-type specific and overlaps in TF pair co-occurrence are highly consistent among related cell types. Furthermore, independently validated co-occurring and directly interacting TFs are significantly enriched in our predictions. Focusing on the regulatory network derived from the predicted co-occurring TF pairs in embryonic stem cells (ESCs) we find that it consists of three subnetworks with distinct functions: maintenance of pluripotency governed by OCT4, SOX2 and NANOG, regulation of early development governed by KLF4, STAT3, ZIC3 and ZNF148 and general functions governed by MYC, TCF3 and YY1. In summary, coTRaCTE predicts highly cell-type specific co-occurring TFs which reveal new insights into transcriptional regulatory mechanisms

coTRaCTE predicts co-occurring transcription factors within cell-type specific enhancers.

Cell-type specific gene expression is regulated by the combinatorial action of transcription factors (TFs). In this study, we predict transcription factor (TF) combinations that cooperatively bind in a cell-type specific manner. We first divide DNase hypersensitive sites into cell-type specifically open vs. ubiquitously open sites in 64 cell types to describe possible cell-type specific enhancers. Based on the pattern contrast between these two groups of sequences we develop "co-occurring TF predictor on Cell-Type specific Enhancers" (coTRaCTE) - a novel statistical method to determine regulatory TF co-occurrences. Contrasting the co-binding of TF pairs between cell-type specific and ubiquitously open chromatin guarantees the high cell-type specificity of the predictions. coTRaCTE predicts more than 2000 co-occurring TF pairs in 64 cell types. The large majority (70%) of these TF pairs is highly cell-type specific and overlaps in TF pair co-occurrence are highly consistent among related cell types. Furthermore, independently validated co-occurring and directly interacting TFs are significantly enriched in our predictions. Focusing on the regulatory network derived from the predicted co-occurring TF pairs in embryonic stem cells (ESCs) we find that it consists of three subnetworks with distinct functions: maintenance of pluripotency governed by OCT4, SOX2 and NANOG, regulation of early development governed by KLF4, STAT3, ZIC3 and ZNF148 and general functions governed by MYC, TCF3 and YY1. In summary, coTRaCTE predicts highly cell-type specific co-occurring TFs which reveal new insights into transcriptional regulatory mechanisms