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Background Fork-head box protein M1 (FOXM1) plays critical roles in development and progression of multiple cancers, including hepatocellular carcinoma (HCC). However, the exact regulatory hierarchy of FOXM1 remains unclear. Here, a genome-wide screen is performed to identify intranuclear proteins that promote FOXM1 transcription activity via liquid–liquid phase separation (LLPS). Results Abnormal spindle-like microcephaly associated (ASPM) is identified to interact with FOXM1 protein via LLPS and enhance its stability by preventing proteasome-mediated degradation. ChIP-sequencing data show ASPM and FOXM1 co-occupy the promoters of multiple genes to promote their transcription, enhancing FOXM1-driven oncogenic progression. In functional experiments, inhibition of ASPM suppresses tumor growth of HCC cells in vivo and in vitro, while overexpression of ASPM has opposite effects. Importantly, reconstitution of FOXM1 partially compensates for the weakened proliferative capacity of HCC cells caused by ASPM silencing. Intriguingly, FOXM1 binds to the promoter region of ASPM and transcriptionally activates ASPM expression in HCC cells. Furthermore, we find that a higher co-expression of ASPM and FOXM1 significantly correlates with poor prognosis in HCC patients. It indicates a double positive feedback loop between ASPM and FOXM1 which coordinately promotes the aggressive progression of HCC. Conclusions Collectively, we demonstrate that LLPS and transcriptional regulation form an oncogenic double positive feedback loop between ASPM and FOXM1. This provides a rationale strategy to treat HCC by targeting this mechanism.

Many types of multiple positive feedbacks with each having potentials to generate bistability exist extensively in natural, raising the question of why a particular architecture is present in a cell. In this study, the authors investigate multiple positive feedback loops across three classes: one-loop class, two-loop class and three-loop class, where each class is composed of double positive feedback loop (DPFL) or double negative feedback loop (DNFL) or both. Through large-scale sampling and robustness analysis, the authors find that for a given class, the homogeneous DPFL circuit (i.e. the coupled circuit that is composed of only DPFLs) is more robust than all the other circuits in generating bistable behaviour. In addition, stochastic simulation shows that the low stable state is more robust than the high stable state in homogeneous DPFL whereas the high-stable state is more robust than the low-stable state in homogeneous DNFL circuits. It was argued that this investigation provides insight into the relationship between robustness and network architecture.

Understanding the dynamical hallmarks of network motifs is one of the fundamental aspects of systems biology. Positive feedback loops constituting one or two nodes – self-activation, toggle switch, and double activation loops – are the commonly observed motifs in regulatory networks underlying cell-fate decision systems. Their individual dynamics are well studied; they are capable of exhibiting bistability. However, studies across various biological systems suggest that such positive feedback loops are interconnected with one another, and design principles of coupled bistable motifs remain unclear. What happens to the bistability or multistability traits and the phenotypic space (collection of phenotypes exhibited by a system) due to the couplings? In this study, we explore a set of such interactions using discrete and continuous simulation methods. Our results suggest that the most frequent states in coupled networks follow the ‘rules’ within a motif (double activation, toggle switch) and those across the two motifs in terms of how the two motifs have been coupled. Moreover, ‘hybrid’ states can be observed, too, where one of the above-mentioned ‘rules’ can be compromised, leading to a more diverse phenotypic repertoire. Furthermore, adding direct and indirect self-activations to these coupled networks can increase the frequency of multistability. Thus, our observations revealed specific dynamical traits exhibited by various coupled bistable motifs.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance 1 – 4 . This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies 5 – 8 , but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3′ untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy. Retroelements located in antisense orientation within interferon-regulated genes are reactivated in a subset of cancer cells and initiate a STING- and MAVS-dependent feed-forward inflammatory loop, driving antitumor immunity and exhaustion.

The ataxia-telangiectasia mutated (ATM) kinase, an upstream kinase of the DNA damage response (DDR), is rapidly activated following DNA damage, and phosphorylates its downstream targets to launch DDR signaling. However, the mechanism of ATM activation is still not completely understood. Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. Monoufmylated histone H4 is important for Suv39h1 and Tip60 recruitment. Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop. These findings reveal that ufmylation of histone H4 by UFL1 is an important step for amplification of ATM activation and maintenance of genomic integrity. Ufmylation is a ubiquitylation-like protein modification but only a few ufmylation substrates and functions have been discovered so far. Here, the authors demonstrate ufmylation of histone H4 upon DNA damage and show that this modification is involved in the amplification of ATM activation.

Recombination, along with sister chromatid cohesion, is used during meiosis to physically connect homologous chromosomes so that they can be segregated properly at the first meiotic division. Recombination is initiated by the introduction of programmed double strand breaks (DSBs) into the genome, a subset of which is processed into crossovers. In budding yeast, the regulation of meiotic DSB repair is controlled by a meiosis-specific kinase called Mek1. Mek1 kinase activity promotes recombination between homologs, rather than sister chromatids, as well as the processing of recombination intermediates along a pathway that results in synapsis of homologous chromosomes and the distribution of crossovers throughout the genome. In addition, Mek1 kinase activity provides a readout for the number of DSBs in the cell as part of the meiotic recombination checkpoint. This checkpoint delays entry into the first meiotic division until DSBs have been repaired by inhibiting the activity of the meiosis-specific transcription factor Ndt80, a site-specific DNA binding protein that activates transcription of over 300 target genes. Recent work has shown that Mek1 binds to Ndt80 and phosphorylates it on multiple sites, including the DNA binding domain, thereby preventing Ndt80 from activating transcription. As DSBs are repaired, Mek1 is removed from chromosomes and its activity decreases. Loss of the inhibitory Mek1 phosphates and phosphorylation of Ndt80 by the meiosis-specific kinase, Ime2, promote Ndt80 activity such that Ndt80 transcribes its own gene in a positive feedback loop, as well as genes required for the completion of recombination and entry into the meiotic divisions. Mek1 is therefore the key regulator of meiotic recombination in yeast.

The two-wheeled robot is a nonlinear system of multi-variables, higherorder and strong coupling. This paper presented a PID Controller with Double Loops (PCDL) to control the tilt angle and velocity of a two-wheeled robot. The angle controller is the regular negative feedback, while the velocity control is the positive feedback. The Double Loops work cooperatively to endow the system with strong anti-interference ability. The stability of the whole system is analyzed and the criterion of the system stability is developed. The simulation and experiments showed that the two-wheeled robot can self-balance and move at an expected velocity and the system has strong anti-interference ability.