A unified-field theory of genome organization and gene regulation

TL;DR

This paper introduces a unified model of genome organization that predicts gene activity based on 3D proximity of promoters to regulatory clusters, reconciling simple and complex regulatory phenomena across human cell types.

Contribution

The paper presents a parsimonious 3D genome model and a proximity-based formula for predicting transcriptional activity, applicable across organisms and cell types.

Findings

A simple proximity formula predicts transcriptional activity in human cells.

The model reconciles simple and complex gene regulation mechanisms.

3D polymer simulations support the model's predictions.

Abstract

Our aim is to predict how often genic and non-genic promoters fire within a cell. We first review a parsimonious pan-genomic model for genome organization and gene regulation, where transcription rate is determined by proximity in 3D space of promoters to clusters containing appropriate factors and RNA polymerases -- structures variously called transcription factories, hubs, and condensates. This model allows reconciliation of conflicting results indicating that regulatory mammalian networks are both simple (as over-expressing just 4 transcription factors switches cell state) and complex (as genome-wide association studies show phenotypes like cell type are determined by thousands of loci rarely encoding such factors). It also yields simple explanations of how mysterious motifs like quantitative trait loci, enhancers, and silencers work. We then present 3D polymer simulations, and a proximity formula based on our biological model that enables prediction of transcriptional activities of all promoters in three human cell types. This simple fitting-free formula contains just one variable (distance on the genetic map to the nearest active promoter), and we suggest it can be applied to any organism.