Quiescence Through the Prism of Evolution

Being able to reproduce and survive is fundamental to all forms of life. In primitive unicellular organisms, the emergence of quiescence as a reversible proliferation arrest has most likely improved cell survival under unfavorable environmental conditions. During evolution, with the repeated appearances of multicellularity, several aspects of unicellular quiescence were conserved while new quiescent cell intrinsic abilities arose. We propose that the formation of a microenvironment by neighboring cells has allowed disconnecting quiescence from nutritional cues. In this new context, non-proliferative cells can stay metabolically active, potentially authorizing the emergence of new quiescent cell properties, and thereby favoring cell specialization. Through its co-evolution with cell specialization, quiescence may have been a key motor of the fascinating diversity of multicellular complexity.

Taiji-reprogram: a framework to uncover cell-type specific regulators and predict cellular reprogramming cocktails

Cellular reprogramming is a promising technology to develop disease models and cell-based therapies. Identification of the key regulators defining the cell type specificity is pivotal to devising reprogramming cocktails for successful cell conversion but remains a great challenge. Here, we present a systems biology approach called Taiji-reprogram to efficiently uncover transcription factor (TF) combinations for conversion between 154 diverse cell types or tissues. This method integrates the transcriptomic and epigenomic data to construct cell-type specific genetic networks and assess the global importance of TFs in the network. Comparative analysis across cell types revealed TFs that are specifically important in a particular cell type and often tightly associated with cell-type specific functions. A systematic search of TFs with differential importance in the source and target cell types uncovered TF combinations for desired cell conversion. We have shown that Taiji-reprogram outperformed the existing methods to better recover the TFs in the experimentally validated reprogramming cocktails. This work not only provides a comprehensive catalog of TFs defining cell specialization but also suggests TF combinations for direct cell conversion.

Multiple and Overlapping Functions of Quorum Sensing Proteins for Cell Specialization in Bacillus Species

ABSTRACT In bacterial populations, quorum sensing (QS) systems participate in the regulation of specialization processes and regulate collective behaviors that mediate interactions and allow survival of the species. In Gram-positive bacteria, QS systems of the RRNPP family (Rgg, Rap, NprR, PlcR, and PrgX) consist of intracellular receptors and their cognate signaling peptides. Two of these receptors, Rap and NprR, have regained attention in Bacillus subtilis and the Bacillus cereus group. Some Rap proteins, such as RapH and Rap60, are multifunctional and/or redundant in function, linking the specialization processes of sporulation and competence, as well as global expression changes in the transition phase in B. subtilis. NprR, an evolutionary intermediate between Rap and RRNPP transcriptional activators, is a bifunctional regulator that modulates sporulation initiation and activates nutrient scavenging genes. In this review, we discuss how these receptors switch between functions and connect distinct signaling pathways. Based on structural evidence, we propose that RapH and Rap60 should be considered moonlighting proteins. Additionally, we analyze an evolutionary and ecological perspective to understand the multifunctionality and functional redundancy of these regulators in both Bacillus spp. and non-Bacillus Firmicutes. Understanding the mechanistic, structural, ecological, and evolutionary basis for the multifunctionality and redundancy of these QS systems is a key step for achieving the development of innovative technologies for health and agriculture.

Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers

Rapid advances in technology are revealing previously unknown organization, cooperation, and limitations within the population of nontumor cells surrounding the tumor epithelium known as the tumor microenvironment (TME). Nowhere are these findings more pertinent than in the gastrointestinal (GI) tract where exquisite cell specialization supports a complex microenvironmental niche characterized by rapid stemness-associated cell turnover, pathogen sensing, epithelial orchestration of immune signaling, and other facets that maintain the complex balance between homeostasis, inflammation, and disease. Here, we summarize and discuss select emerging concepts in the precancerous microenvironment, TME, and tumor epithelial-TME crosstalk as well as their implications for the management of GI cancers.