How human-derived brain organoids are built differently from brain organoids derived from genetically-close relatives: A multi-scale hypothesis

Abstract

How genes influence tissue-scale organization remains a longstanding biological puzzle. While experimental efforts quantify gene expression, chromatin, cellular, and tissue structure, computational models lag behind. To help accelerate multiscale modeling, we demonstrate how a tissue-scale, cellular-based model can be merged with a cell nuclear model incorporating a deformable lamina shell and chromatin to test hypotheses linking chromatin and tissue scales. Specifically, we propose a hypothesis to explain structural differences between human, chimpanzee, and gorilla-derived brain organoids. Recent experiments reveal that a cell fate transition from neuroepithelial to radial glial cells includes a new intermediate state that is delayed in human-derived organoids, leading to significantly narrowed and lengthened apical cells. Additional experiments also demonstrated that ZEB2, a transcription factor, plays a major role in the onset of the novel intermediate state. We hypothesize that this delay stems from chromatin reorganization triggered by mechanical strain as the respective brain organoids develop, with a higher critical threshold in human-derived cells. Here, we computationally test the feasibility of such a hypothesis by exploring how slightly different initial configurations of chromatin, as modeled by different numbers of chromatin crosslinkers, organize in response to mechanical strain with increasingly different initial configurations representing less genetically-close relatives. We find that even small differences in the number of chromatin crosslinkers (> 0.01%) yield distinguishable chromatin displacement on average beyond 35% mechanical strain. At higher strains, we observe a new type of nonlinear chromatin scaling law with an exponent of 3.24(5). Finally, we show how differences in chromatin strain maps and more conventional contact maps can reveal structural distinctions between genetically-close species.