# Tissue-specific atlas of trans-models for gene regulation elucidates complex regulation patterns

## TL;DR

This study creates a detailed map of how transcription factors regulate genes in 49 tissues, revealing complex patterns linked to diseases and drug responses.

## Contribution

A novel tissue-specific atlas of trans-models for gene regulation across 49 tissues, capturing combinatorial and genetic variant-based mechanisms.

## Key findings

- Tissue similarity based on regulated genes aligns with other tissue similarity measures.
- Regulated genes are enriched for pharmacogenomic functions and cancer/metabolic pathways.
- Multilevel regulation by TFs across tissues reveals tissue-specific and immune-related gene functions.

## Abstract

Deciphering gene regulation is essential for understanding the underlying mechanisms of healthy and disease states. While the regulatory networks formed by transcription factors (TFs) and their target genes has been mostly studied with relation to cis effects such as in TF binding sites, we focused on trans effects of TFs on the expression of their transcribed genes and their potential mechanisms.

We provide a comprehensive tissue-specific atlas, spanning 49 tissues of TF variations affecting gene expression through computational models considering two potential mechanisms, including combinatorial regulation by the expression of the TFs, and by genetic variants within the TF.

We demonstrate that similarity between tissues based on our discovered genes corresponds to other types of tissue similarity. The genes affected by complex TF regulation, and their modelled TFs, were highly enriched for pharmacogenomic functions, while the TFs themselves were also enriched in several cancer and metabolic pathways. Additionally, genes that appear in multiple clusters are enriched for regulation of immune system while tissue clusters include cluster-specific genes that are enriched for biological functions and diseases previously associated with the tissues forming the cluster. Finally, our atlas exposes multilevel regulation across multiple tissues, where TFs regulate other TFs through the two tested mechanisms.

Our tissue-specific atlas provides hierarchical tissue-specific trans genetic regulations that can be further studied for association with human phenotypes.

The online version contains supplementary material available at 10.1186/s12864-024-10317-y.