Hierarchical cell identities emerge from animal gene regulatory mechanisms

TL;DR

This paper develops a mathematical model showing that hierarchical cell identities in animals emerge from enhancer competition and epigenetic regulation, explaining lineage relationships and dysregulation in cancer.

Contribution

It introduces a predictive mathematical theory linking epigenetic mechanisms to hierarchical cell identities and lineage dynamics in animal development.

Findings

Hierarchical identities arise from enhancer competition and epigenetic interactions.

The model predicts blood progenitor relationships and cell identity dysregulation.

Modulation of enhancer competition influences developmental and cancer processes.

Abstract

The hierarchical organisation of cell identity is a fundamental feature of animal development with rich and well-characterized experimental phenomenology, yet the mechanisms driving its emergence remain unknown. The regulation of cell identity genes relies on a distinct mechanism involving higher-order interactions of transcription factors on distant regulatory regions called enhancers. These interactions are mediated by epigenetic regulators that are broadly shared between enhancers. Through the development of a new and predictive mathematical theory on the effects of epigenetic regulator activity on gene network dynamics, we demonstrate that hierarchical identities are essential emergent properties of animal-specific gene regulatory mechanisms. Hierarchical identities arise from the interplay between enhancer competition for epigenetic readers and cooperation through activation of shared transcriptional programs. We show that epigenetic regulatory mechanisms provide the network with self-similar properties that enable multilineage priming and signal-dependent control of progenitor states. The stabilisation of progenitor states is predicted to be controlled by the balance in activities between epigenetic writers and erasers. Our model quantitatively predicts lineage relationships, reconstructs all known blood progenitor states from terminal states, and explains mechanisms of cell identity dysregulation in cancer and the general differentiation effects of histone deacetylase inhibition. We identify non-specific modulation of enhancer competition as a central regulatory axis, with implications for developmental biology, cancer, and differentiation therapy.