Non-genetic control of cell plasticity and phenotypic cell states is mediated by cytoplasmic IncRNA nucleated signalling pathways

Cell plasticity, the ability that cells display to rapidly adapt to environmental cues, is thought to be encoded in non-genetic information reservoirs. Although the notion is widely acknowledged, the molecular details underlying this phenomenon remain largely concealed. Herein, we show that clonal cell populations inherently display multiple co-existing metastable gene expression states that co-segregate with various phenotypic outputs. Moreover, we provide primer evidence suggesting that transcriptome states are inherited, dynamically interconvert and determine phenotypic output upon a variety of biological cues, not as a result of transcriptional shifts, but rather through yet unidentified post-transcriptional mechanisms. Remarkably, among phenotypically divergent clonal cell populations enriched in subsets of transcriptome states, we identified a peri-nuclear cytoplasmic structure (Signal Integration Portal - SIP) where state-specific lncRNAs, proteins harbouring intrinsically disordered regions and various active signalling pathways converge. Herein, we propose that SIP-condensates act as nucleating reservoir of non-genetic information at the crossroads of cell plasticity and non-genetic heterogeneity where they integrate intra- and extracellular inputs thereby moulding phenotypic output.