2024/12/15 by Anton Grishechkin, Grishechkin, Anton, Abhirup Mukherjee +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · Computer Science · Neuroscience · #Cell Behavior (q-bio.CB) #FOS: Biological sciences #Memory and Neural Mechanisms #Molecular Networks (q-bio.MN) #Neural Networks and Applications #Neural dynamics and brain function #q-bio.CB #q-bio.MN
paper · pdf · doi:10.48550/arxiv.2412.11336
openalex publication_date 2024/12/15 · arxiv published 2024/12/15 · openalex created_date 2024/12/18 · arxiv updated 2025/04/05 · openalex updated_date 2026/07/28
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.