Changes in gene expression are thought to regulate the cell differentiation process intrinsically through complex epigenetic mechanisms. In fundamental terms, however, this assumed regulation refers only to the intricate propagation of changes in gene expression or else leads to non-explanatory regresses. The developmental self-regulatory dynamics and evolution of individuated multicellular organisms also lack a unified and falsifiable description. To fill this gap, I computationally analyzed publicly available high-throughput data of histone H3 post-translational modifications and mRNA abundance for different Homo sapiens, Mus musculus, and Drosophila melanogaster cell-type/developmental-period samples. My analysis of genomic regions adjacent to transcription start sites generated a profile from pairwise partial correlations between histone modifications controlling for the respective mRNA levels for each cell-type/developmental-period dataset. I found that these profiles, while explicitly uncorrelated with the respective transcriptional “identities” by construction, associate strongly with cell differentiation states. This association is not expected if cell differentiation is, in effect, regulated by epigenetic mechanisms. Based on these results, I propose a general, falsifiable theory of individuated multicellularity, which relies on the synergistic coupling across the extracellular space of two explicitly uncorrelated “self-organizing” systems constraining histone modification states at the same sites. This theory describes how the simplest multicellular individual—understood as an intrinsic, higher-order constraint—emerges from proliferating undifferentiated cells, and could explain the intrinsic regulation of gene transcriptional changes for cell differentiation and the evolution of individuated multicellular organisms.

Felipe article