PT - JOURNAL ARTICLE AU - Felipe A. Veloso TI - A General Theory of Differentiated Multicellularity AID - 10.1101/016840 DP - 2015 Jan 01 TA - bioRxiv PG - 016840 4099 - http://biorxiv.org/content/early/2015/07/27/016840.short 4100 - http://biorxiv.org/content/early/2015/07/27/016840.full AB - Scientists agree that changes in the levels of gene expression are important for the cell differentiation process. Research in the field has customarily assumed that such changes regulate this process when they interconnect in space and time by means of 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 logical inconsistencies. The evolution and intrinsic regulatory dynamics of differentiated multicellularity also lack a unified and falsifiable description. To fill this gap, I 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. An analysis of genomic regions adjacent to transcription start sites generated for each cell-type/developmental-period dataset a profile from pairwise partial correlations between histone modifications controlling for the respective mRNA levels. Here I report that these profiles, while explicitly uncorrelated to transcript abundance 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 theory of differentiated multicellularity, which relies on the synergistic coupling across the extracellular space of two stochastically independent “self-organizing” systems constraining histone modification states at the same sites. This theory describes how the differentiated multicellular organism—understood as an intrinsic, higher-order, self-sufficient, self-repairing, self-replicating, and self-regulating constraint—emerges from proliferating undifferentiated cells. If it resists falsification, this theory will explain the intrinsic regulation of gene transcriptional changes during cell differentiation and the emergence of differentiated multicellular lineages throughout evolution.Abbreviations:H. sapiens6 cell types: HSMM (skeletal muscle myoblasts), HUVEC (umbilical vein endothelial cells), NHEK (epidermal keratinocytes), GM12878 (B-lymphoblastoids), NHLF (lung fibroblasts) and H1-hESC (embryonic stem cells).9 histone H3 modifications: H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me3, H3K27ac, H3K27me3, H3K36me3, and H3K79me2.M. musculus5 cell types: 8-weeks-adult heart, 8-weeks-adult liver, E14-day0 (embryonic stem cells after zero days of differentiation), E14-day4 (embryonic stem cells after four days of differentiation), and E14-day6 (embryonic stem cells after six days of differentiation).5 histone H3 modifications: H3K4me1, H3K4me3, H3K27ac, H3K27me3, and H3K36me3.D. melanogaster9 cell samples: 0-4h embryos, 4-8h embryos, 8-12h embryos, 12-16h embryos, 16-20h embryos, 20-24h embryos, L1 larvae, L2 larvae, and pupae.6 histone H3 modifications: H3K4me1, H3K4me3, H3K9ac, H3K9me3, H3K27ac, and H3K27me3.