Abstract
Transcription factors (TFs) exert their regulatory action by binding to DNA with specific sequence preferences. However, different TFs can partially share their binding sequences due to their common evolutionary origin. This “redundancy” of binding defines a way of organizing TFs in “motif families” by grouping TFs with similar binding preferences. Since these ultimately define the TF target genes, the motif family organization entails information about the structure of transcriptional regulation as it has been shaped by evolution. Focusing on the human TF repertoire, we show that a one-parameter evolutionary model of the Birth-Death-Innovation type can explain the TF empirical repartition in motif families, and allows to highlight the relevant evolutionary forces at the origin of this organization. Moreover, the model allows to pinpoint few deviations from the neutral scenario it assumes: three over-expanded families (including HOX and FOX genes), a set of “singleton” TFs for which duplication seems to be selected against, and a higher-than-average rate of diversification of the binding preferences of TFs with a Zinc Finger DNA binding domain. Finally, a comparison of the TF motif family organization in different eukaryotic species suggests an increase of redundancy of binding with organism complexity.
Highlights
Transcriptional regulation plays a crucial role in most physiological processes, ranging from cell homeostasis to differentiation[1,2,3], and its disregulation is often implicated in pathological processes such as cancer[4]
Transcriptional regulation is mainly controlled by a class of proteins known as transcription factors (TFs) which are characterized by the presence of at least one DNA binding domain (DBD), i.e., a structural domain able to mediate the TF-DNA interaction
Leveraging on this remarkable progress, we propose here a classification of TFs based on their binding preferences, following the approach of Jolma et al.[28]. The result of this classification is an organization of TFs in what we call motif families, which group together TFs associated to the same PWM. This organization in motif families is a sub-partition of the DBD classification, which is expected to be more closely related to the TF regulatory potential and to evolutionary forces which shaped the regulatory network
Summary
Transcriptional regulation plays a crucial role in most physiological processes, ranging from cell homeostasis to differentiation[1,2,3], and its disregulation is often implicated in pathological processes such as cancer[4]. Gene gain and loss seem to account for a large part of the human/ chimpanzee genetic divergence[22, 23] These basic evolutionary moves of duplication and deletion can significantly alter the transcriptional regulatory network by expanding or reducing the number of TFs with certain specific binding preferences. A duplication event expands a TF family, while the progressive sequence divergence of a TF may give rise to a new TF family able to recognize a significantly different set of target genes These dynamics could be typically dominated by neutral evolution, but the TF organization may conceal hallmarks of adaptive selection that, for example, drove the over-expansion of specific TFs or their functional diversification. The model introduces a natural measure of TF binding redundancy, and by comparing several eukaryotic model species a striking evolutionary trend can be identified
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