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

Abstract: How genes affect tissue scale organization remains a longstanding biological puzzle. As experimental efforts aim to quantify gene expression, chromatin organization, cellular structure, and tissue structure, computational modeling lags behind. To address this gap, we merge a cellular-based tissue model with a nuclear model that includes a deformable lamina shell and chromatin to test multiscale hypotheses linking chromatin and tissue scales. We propose a multiscale hypothesis focusing on brain organoids to explain structural differences between brain organoids built from induced-pluripotent human stem cells and induced-pluripotent gorilla and chimpanzee cells. Recent experiments discover that a cell fate transition from neuroepithelial to radial glial cells includes a new intermediate state delayed in human organoids, which narrows and lengthens cells on the apical side. Experiments show that the transcription factor ZEB2 plays a major role in the emergence of this intermediate state with ZEB2 mRNA levels peaking. We postulate that the enhancement of ZEB2 expression is potentially due to chromatin reorganization in response to mechanical deformations of the nucleus. A larger critical mechanical strain triggers reorganization in human-derived stem cells, causing delayed ZEB2 upregulation compared with genetically close relatives. We test this by exploring how slightly different initial configurations of chromatin reorganize under applied strain, with greater representing less genetically-close relatives. We find that larger configuration discrepancies produce increased differences in the magnitude of chromatin displacement that rise faster than linearly yet slower than exponentially. Changes in chromatin strain and contact maps can reveal species-specific differences, aiding our understanding of how one species differs in structure from another.