Yeast cell fate control by temporal redundancy modulation of transcription factor paralogs

Recent single-cell studies have revealed that yeast stress response involves transcription factors that are activated in pulses. However, it remains unclear whether and how these dynamic transcription factors temporally interact to regulate stress survival. Here we show that budding yeast cells can exploit the temporal relationship between paralogous general stress regulators, Msn2 and Msn4, during stress response. We find that individual pulses of Msn2 and Msn4 are largely redundant, and cells can enhance the expression of their shared targets by increasing their temporal divergence. Thus, functional redundancy between these two paralogs is modulated in a dynamic manner to confer fitness advantages for yeast cells, which might feed back to promote the preservation of their redundancy. This evolutionary implication is supported by evidence from Msn2/Msn4 orthologs and analyses of other transcription factor paralogs. Together, we show a cell fate control mechanism through temporal redundancy modulation in yeast, which may represent an evolutionarily important strategy for maintaining functional redundancy between gene duplicates.

The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip

The single-layered, simple epithelium of the gastro-intestinal tract controls nutrient uptake, coordinates our metabolism and shields us from pathogens. Despite its seemingly simple architecture, the intestinal lining consists of highly distinct cell populations that are continuously renewed by the same stem cell population. The need to maintain balanced diversity of cell types in an unceasingly regenerating tissue demands intricate mechanisms of spatial or temporal cell fate control. Recent advances in single-cell sequencing, spatio-temporal profiling and organoid technology have shed new light on the intricate micro-structure of the intestinal epithelium and on the mechanisms that maintain it. This led to the discovery of unexpected plasticity, zonation along the crypt-villus axis and new mechanism of self-organization. However, not only the epithelium, but also the underlying mesenchyme is distinctly structured. Several new studies have explored the intestinal stroma with single cell resolution and unveiled important interactions with the epithelium that are crucial for intestinal function and regeneration. In this review, we will discuss these recent findings and highlight the technologies that lead to their discovery. We will examine strengths and limitations of each approach and consider the wider impact of these results on our understanding of the intestine in health and disease.

Depletion of kinesin motor KIF20A to target cell fate control suppresses medulloblastoma tumour growth

During mammalian brain development, neural progenitor cells proliferate extensively but can ensure the production of correct numbers of various types of mature cells by balancing symmetric proliferative versus asymmetric differentiative cell divisions. This process of cell fate determination may be harnessed for developing cancer therapy. Here, we test this idea by targeting KIF20A, a mitotic kinesin crucial for the control of cell division modes, in a genetic model of medulloblastoma (MB) and human MB cells. Inducible Kif20a knockout in both normal and MB-initiating granule neuron progenitors (GNPs) causes early cell cycle exit and precocious neuronal differentiation without causing cytokinesis failure and suppresses the development of Sonic Hedgehog (SHH)-activated MB. Inducible KIF20A knockdown in human MB cells inhibits proliferation both in cultures and in growing tumors. Our results indicate that targeting the fate specification process of nascent daughter cells presents a novel avenue for developing anti-proliferation treatment for malignant brain tumors.

Synthetic multistability in mammalian cells

In multicellular organisms, gene regulatory circuits generate thousands of molecularly distinct, mitotically heritable states, through the property of multistability. Designing synthetic multistable circuits would provide insight into natural cell fate control circuit architectures and allow engineering of multicellular programs that require interactions among cells in distinct states. Here we introduce MultiFate, a naturally-inspired, synthetic circuit that supports long-term, controllable, and expandable multistability in mammalian cells. MultiFate uses engineered zinc finger transcription factors that transcriptionally self-activate as homodimers and mutually inhibit one another through heterodimerization. Using model-based design, we engineered MultiFate circuits that generate up to seven states, each stable for at least 18 days. MultiFate permits controlled state-switching and modulation of state stability through external inputs, and can be easily expanded with additional transcription factors. Together, these results provide a foundation for engineering multicellular behaviors in mammalian cells.

The Role of Necroptosis: Biological Relevance and Its Involvement in Cancer

Regulated cell death mechanisms are essential for the maintenance of cellular homeostasis. Evasion of cell death is one of the most important hallmarks of cancer. Necroptosis is a caspase independent form of regulated cell death, investigated as a novel therapeutic strategy to eradicate apoptosis resistant cancer cells. The process can be triggered by a variety of stimuli and is controlled by the activation of RIP kinases family as well as MLKL. The well-studied executor, RIPK1, is able to modulate key cellular events through the interaction with several proteins, acting as strategic crossroads of several molecular pathways. Little evidence is reported about its involvement in tumorigenesis. In this review, we summarize current studies on the biological relevance of necroptosis, its contradictory role in cancer and its function in cell fate control. Targeting necroptosis might be a novel therapeutic intervention strategy in anticancer therapies as a pharmacologically controllable event.

Ubiquitin-dependent and -independent functions of OTULIN in cell fate control and beyond

Ubiquitination, and its control by deubiquitinating enzymes (DUBs), mediates protein stability, function, signaling and cell fate. The ovarian tumor (OTU) family DUB OTULIN (FAM105B) exclusively cleaves linear (Met1-linked) poly-ubiquitin chains and plays important roles in auto-immunity, inflammation and infection. OTULIN regulates Met1-linked ubiquitination downstream of tumor necrosis factor receptor 1 (TNFR1), toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) receptor activation and interacts with the Met1 ubiquitin-specific linear ubiquitin chain assembly complex (LUBAC) E3 ligase. However, despite extensive research efforts, the receptor and cytosolic roles of OTULIN and the distributions of multiple Met1 ubiquitin-associated E3-DUB complexes in the regulation of cell fate still remain controversial and unclear. Apart from that, novel ubiquitin-independent OTULIN functions have emerged highlighting an even more complex role of OTULIN in cellular homeostasis. For example, OTULIN interferes with endosome-to-plasma membrane trafficking and the OTULIN-related pseudo-DUB OTULINL (FAM105A) resides at the endoplasmic reticulum (ER). Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin-dependent and -independent functions.