Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system

In single cells, variably sized nanoscale chromatin structures are observed but it is unknown if these form a cohesive framework that regulates RNA transcription. Herein we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally-defined heterogenous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion. We show that packing domains are not topologically associated domains. Instead, packing domains exist across a structure-function life-cycle that couples heterochromatin and transcription in situ, explaining how heterochromatin enzyme inhibition can produce a paradoxical decrease in transcription by destabilizing domain cores. Applied to development and aging, we show the pairing of heterochromatin and transcription at myogenic genes that could be disrupted by nuclear swelling. In sum, packing domains represent a foundation to explore the interactions of chromatin and transcription at the single cell level in human health.

Methods
The data was collected across a range of techniques including chromatin scanning transmission electron microscopy (ChromSTEM), multiplexed single molecule localization microscopy (SMLM), partial wave spectroscopic (PWS) microscopy), Hi-C, and ChIP-Seq. Details of the collection and analysis are within the materials and methods of the manuscript for each method.