Global stabilizing control of large-scale biomolecular regulatory networks.

Motivation: Cellular behavior is determined by complex non-linear interactions between numerous intracellular molecules that are often represented by Boolean network models. To achieve a desired cellular behavior with minimal intervention, we need to identify optimal control targets that can drive heterogeneous cellular states to the desired phenotypic cellular state with minimal node intervention. Previous attempts to realize such global stabilization were based solely on either network structure information or simple linear dynamics.

PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression.

Although stromal fibroblasts play a critical role in cancer progression, their identities remain unclear as they exhibit high heterogeneity and plasticity. Here, a master transcription factor (mTF) constructing core-regulatory circuitry, PRRX1, which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. PRRX1 orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-β signaling by remodeling a super-enhancer landscape.

Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts.

Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence.

A positive feedback loop bi-stably activates fibroblasts.

Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC).