Cooperation of transposable elements to endow global networks of initiators of hybrid assembly pathways of endogenous multiprotein complexes.

Mechanisms governing initiation steps of the assembly of endogenous multi-protein complexes (EMC) remain incompletely understood. Here, multiple lines of observations are reported describing the function-aligned initiation sequence of hybrid assembly pathways (HAP) of EMC. The first step of HAP-guided chain reactions of protein-protein interactions (PPI) of EMC assemblies constitutes the creation of cell type-specific pools of hetero and homo dimers. The molecular anatomy of HAP was elucidated by defining qualitative and quantitative characteristics of protein binding to a compendium of 200,393 distinct genomic regulatory elements (GRE), including 49,667 sequences representing control sets of genomic loci as well as 150,726 GRE of different evolutionary origins. The consensus sequence of HAP actions consists of: a) Initiation on genomic DNA of the formation of metastable hetero- and homodimers of EMCs' protein constituents; b) Release of dimers from DNA templates for delivery to the EMC assembly compartments; c) Assembly of defined EMC by sequential on demand addition of proteins to preformed dimers serving as attractors of EMC-specific ensembles of monomers. Chromosome-naïve DNA scaffolds facilitating creation of intracellular dimer pools engage networks of ~700 transcription factors (TFs), 534 of which manifest region-specific patterns of significantly enriched expression in 1358 brain regions. HAP initiators appear to operate within nucleosome-depleted islands of transposable elements (TE) - derived sequences within heterochromatin. PPI assembly lines of EMCs operate in 2 concurrent modes: TF-TF PPI cascade and PPI HUB protein cascade. Regardless of the number of DNA-bound initiator TFs (ranging from one to 716 TFs), both modes of operations reached the equilibrium at the PPI constituents saturation levels of ~245 proteins for TF-TF PPI modes and of ~351 proteins for PPI HUB protein modes. Distinct panels of DNA-bound initiator TFs and proteins of PPI cascade ensembles are enriched in either defined sets of neuroanatomical structures (TF-TF mode) or among structural-functional constituents of synapses (HUB proteins mode). Thus, these bifurcated cascades appear biologically congruent: TF-TF constituents map to transcriptional signatures of hundreds of brain regions, whereas HUB constituents map to synaptogenesis and synaptic structures, suggesting the unified logic of genomic functions coordinating region identity and connectivity. Evidence-supported examples of default operations of PPI-guided assemblies of hetero- and homodimers of Yamanaka factors, neurogenesis constituents, and protein components of postsynaptic density of excitatory and inhibitory synaptogenesis are reported with detailed analytical focus on human Claustrum. The foundational set of observations reported in this contribution should facilitate experimental and theoretical explorations of TE-seeded genomic codes for initiators of PPI chain reactions of protein dimerization creating pools of attractors to guide and accelerate the EMC assemblies.