Hierarchical cell identity control by collective enhancer dynamics

The hierarchical organization of cell identity, characterized by progenitor cells coexpressing multiple transcriptional programs, is a hallmark of animal development with well-documented experimental phenomenology. However, the mechanisms underlying its emergence remain unclear. Here we investigate the origin and regulation of progenitor states using a mechanistic mathematical framework based on transcription factor-enhancer interactions. This framework maps the regulation of cell identity genes to the dynamics of a continuous Modern Hopfield network, governed by an inverse-temperature-like parameter,  β, representing epigenetic modifier activity, and an input field, w , reflecting signaling activity. 

We propose that multilineage-primed progenitor states emerge from the interplay between enhancer competition for epigenetic readers and the activation of overlapping transcriptional programs. Mathematically, these progenitor states correspond to mixed attractor patterns in the network at intermediate values. We introduce an analytical approach to characterize the identity, stability, and basins of attraction of progenitor states, including their emergence and destabilization at specific  thresholds. 

Applying this approach, we explain how signalling can instruct differentiation, reconstruct the complex blood progenitor landscape from terminal lineages, and identify potential mechanisms of differentiation dysregulation in cancer. We propose that nonspecific modulation of enhancer competition is a key regulatory axis underlying cell identity transitions.

Venue: Fulton G20