Encounters across networks: Windows into principles of genomic regulation

Abstract

Gene regulatory networks account for the ability of the genome to program development in complex multi-cellular organisms. Such networks are based on principles of gene regulation by combinations of transcription factors that bind to specific cis-regulatory DNA sites to activate transcription. These cis-regulatory regions mediate logic processing at each network node, enabling progressive increases in organismal complexity with development. Gene regulatory network explanations of development have been shown to account for patterning and cell type diversification in fly and sea urchin embryonic systems, where networks are characterized by fast coupling between transcriptional inputs and changes in target gene transcription rates, and crucial cis-regulatory elements are concentrated relatively close to the protein coding sequences of the target genes, thus facilitating their identification. Stem cell-based development in post-embryonic mammalian systems also depends on gene networks, but differs from the fly and sea urchin systems. First, the number of regulatory elements per gene and the distances between regulatory elements and the genes they control are considerably larger, forcing searches via genome-wide transcription factor binding surveys rather than functional assays. Second, the intrinsic timing of network state transitions can be slowed considerably by the need to undo stem-cell chromatin configurations, which presumably add stability to stem-cell states but retard responses to transcription factor changes during differentiation. The dispersed, partially redundant cisregulatory systems controlling gene expression and the slow state transition kinetics in these systems already reveal new insights and opportunities to extend understanding of the repertoire of gene networks and regulatory system logic.

Dynamic chromatin accessibility deploys heterotypic cis/trans-acting factors driving stomatal cell-fate commitment

“…Such heterotypic TF complex is also observed during cardiogenesis, hematopoiesis and myogenesis 9,[55][56][57][58][59] . For instance, heterotypic TF interactions among the T-box TF TBX5, the homoeodomain TF NKX2-5 and the zinc finger TF GATA4 not only coordinate cardiac gene expression, differentiation and morphogenesis, but also mutually limit their potential from binding to developmentally irrelevant regulatory elements in a given context 9,55 .…”

How haematopoiesis research became a fertile ground for regulatory network biology as pioneered by Eric Davidson

“…Despite the powerful influence of Davidson's approaches, there are differences between the network models needed to account for non-vertebrate embryogenesis and for hematopoietic systems in postnatal mammals. These are noted briefly here; for a more detailed review, see [82]. Key differences concern dose dependence and timing.…”

“…This makes direct, indirect, and feed-forward dependent effects hard to disentangle. The slow response may be due in part to epigenetic state inertia, as discussed elsewhere [82,93]. However, it is also possible that hematopoietic gene regulatory networks themselves are more highly buffered against state changes.…”