Know Thy Friends, know ThyselF – Transcription Factor (TF) regulation resolved

A new large scale study on human transcription factors combining two state-of-the art interactomics methods, that allow rapid identification of protein-protein interactions and extensive functional information of this important gene family, generates a vast atlas of TF biology.

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Transcription factors (TFs) are the most essential gene/protein group for the cellular development, differentiation and maintaining homeostasis. They drive complex patterns of gene expression in cells in all stages of development. Defects in TF signalling often lead to developmental disorders and diseases. However, while TF DNA binding has been widely studied, we are still lacking a systems-level understanding on how TF activity and signalling is controlled via their interactions with multiple proteins, such as cofactors, dimerization partners, chromatin modulating proteins, enzymes, inhibitory proteins and general transcription factors. These interactions are key to define the transcriptional output (positive or negative) of the TF (illustrated in Figure 1). Therefore,we decided to initiate this large study to shed some light on TF protein-protein interactions and TF regulation.

An artistic representation of transcriptional regulation of gene expression by transcription factor complexes. The effect of TFs on transcription  can be cell type and situation dependent and is often concerted by their exerted positive and negative effects. 

In our study  (https://www.nature.com/articles/s41467-022-28341-5) on Nature Communication, we introduce a comprehensive interactome analysis of more than 100 TFs, revealing over 7,000 TF protein-protein interactions, most of which are in nuclear and play important roles in transcriptional regulation. The large number of TF interactions discovered in this study enabled us to conduct a systems-level analysis that revealed groups of TFs with specific biological functions, such as chromatin remodelling and RNA splicing.

Interestingly, almost half of the studied TFs interacted with the nuclear factor family of TFs. Nuclear factors are known to control a plethoraof genes and organogenesis during development and their aberrant activity is linked to severalhuman cancer types. Our data suggest that transcription control by NFIs may be regulated by nuclear factor interactions with other TFs.

In summary, the study provides the first comprehensive and complimentary overview of on the physical and functional interactions of thehumantranscription factorsand ourfindings pave the way for further studies on the TF regulation.

We have been for that last 10 years heavily involved in identifying and studying the disease mechanisms of individual transcription factor mutations in cancer and in immunodeficiencies. TFs have proven to be difficult drug targets, however several of their key regulators are much more promising.  We really think that our generated large information atlas on the TFs, would act as a rich resource for also drug discovery studies to identify pharmaceutical treatment for TF-related diseases.

The study was financially supported by the Finnish Academy, University of Helsinki, The Sigrid Juselius Foundation, Instrumentarium Science Foundation, Biocentrum Helsinki and HiLIFE.

Reference:

Helka Göös, Matias Kinnunen, Kari Salokas, Zenglai Tan, Xiaonan Liu, Leena Yadav, Qin Zhang, Gong-Hong Wei & Markku Varjosalo 

Human transcription factor protein interaction networks

Nature Communications

Markku Varjosalo

Research Director, University of Helsinki

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