Hepatocyte nuclear factor 4 alpha (HNF4α) is a conserved nuclear receptor that governs epithelial identity and metabolic homeostasis across endoderm-derived tissues. In cancer, HNF4α can function as either an oncogene or a tumor suppressor. In colorectal and hepatocellular carcinoma, reduced HNF4α activity accompanies loss of differentiation and tumor progression, consistent with tumor-suppressive functions. In contrast, in pancreatic ductal adenocarcinoma, invasive mucinous adenocarcinoma, and other lineage-defined epithelial tumors, HNF4α can also participate in transcriptional programs that sustain malignant identity, metabolic adaptation, and therapeutic resistance. However, these effects are highly context-dependent and do not imply a uniformly oncogenic role in these tumor types. These divergent functions are shaped by isoform usage, chromatin state, epigenetic regulation, metabolic cues, and transcription factor networks. Rather than acting as a classical oncogene or tumor suppressor in all settings, HNF4α is better understood as a context-dependent regulator of lineage state whose activity may either restrain tumor progression or support tumor maintenance. This mini review highlights the molecular mechanisms that shape HNF4α activity, including isoform biology and epigenetic control, and discusses emerging strategies for selectively inhibiting HNF4α in dependency states or restoring its differentiation-promoting functions in tumors where it is lost.

Tunneling nanotubes (TNTs) are thin, actin-based membrane bridges that establish direct cytoplasmic continuity between distant cells, enabling the transfer of diverse cargoes ranging from ions and proteins to organelles such as mitochondria. Since their discovery in 2004, TNTs have been identified in numerous cell types and linked to an expanding range of physiological and pathological functions. Yet, their molecular identity and mechanisms of formation remain elusive. The most defining and least understood step in TNT biogenesis is membrane fusion, the process by which TNTs achieve open-ended continuity between cells, and this represents a critical frontier in the field. This review integrates recent advances in TNT biology, emphasizing the interplay between actin cytoskeletal dynamics, plasma membrane composition, and cell adhesion during TNT formation. It also draws mechanistic parallels with established models of membrane fusion, highlighting fundamental principles and shared regulators across fusion systems, many of which have been implicated in TNT functionality. By combining molecular, biophysical, and imaging perspectives, this review proposes a conceptual framework for TNT formation and fusion, identifies major methodological gaps, and outlines future directions to unravel the mechanisms that underlie intercellular cytoplasmic continuity.

The biorientation-defective (BOD) protein family, comprising BOD1, BOD1L1 (BOD1-like 1), and BOD1L2, plays critical and diverse roles in fundamental cellular processes, including mitosis, DNA repair, neurological function, and metabolism. BOD1 and BOD1L2 are small proteins of less than 200 amino acids, whereas BOD1L1 contains a long C-terminal extension, totaling 3042 amino acids. BOD1 was originally identified in Xenopus laevis oocyte chromatin extracts. Subsequent work in mitotic human cells demonstrated that BOD1 is an outer kinetochore protein that regulates PP2A-B56 phosphatase function and consequently is vital for chromosome biorientation and segregation fidelity, hence the name. BOD1 also has important roles in neurological function and lipid metabolism as a component of the COMPASS (complex of proteins associated with SET1)–SETD1B complex. In contrast, BOD1L1 was first identified as a phosphorylated target of the ATM kinase and then highlighted in a screen for DNA replication fork components. Further work demonstrated a role for BOD1L1 in DNA double-stranded break repair, where BOD1L1 is required to recruit the protein RIF1 to damaged chromatin to enable efficient DNA repair and control sensitivity to radio/chemotherapeutics. Consistently, BOD1L1 binds known DNA damage/repair/replication proteins, including FANCD2, RIF1, and BRCA2. Loss of BOD1L1 causes catastrophic genome instability through misrepair and/or overprocessing of damaged DNA. Recently, BOD1L1 has also been shown to regulate the PP2A-B56 phosphatase at kinetochores in mitotic human cells. In contrast, little is known about BOD1L2, which is only expressed in sperm cells and precursors. In this review, we describe recent progress in understanding the functions of this protein family and discuss future avenues of research.

Eukaryotic DNA has been covalently modified by DNA methylation and folded into a three-dimensional conformation in the nucleus. While the functions of DNA methylation and chromosome organization have been widely discussed, respectively, the interplay between DNA methylation and chromosome organization remains less clear and needs to be further explained. In this review, we first discuss the cross-talk between DNA methylation and chromosome conformation, highlighting the complexity and importance of DNA methylation on chromosome organization. We also summarize the current methodologies that capture DNA methylation and chromosome organization individually or simultaneously in bulk and single cells. These mechanistic and methodological advancements facilitate broad interest in unveiling the interplay between DNA methylation and chromosome organization.

Phosphorylation plays a central role in regulating signal transduction across all kingdoms of life, allowing organisms to sense and respond to their environment. In mammals, the signalling research field is dominated by the functions of pSer, pThr and pTyr, due to both historical and technological factors. Mostly ignored are the labile phosphosites (LaPhs), made up of six other phosphorylatable amino acids: His, Lys, Arg, Asp, Glu and Cys. This group is characterised by an acid and/or heat-labile phosphate linkage, forming a distinct group from the highly stable phosphomonoesters of pSer, pThr and pTyr. LaPhs have distinct thermal and pH stability profiles, which may contribute to, or even dictate, their functions. Here, we review the contribution of LaPhs to mammalian signalling networks, highlighting their currently defined diverse functions.

The MET receptor tyrosine kinase is a pivotal regulator of cellular survival, motility, and proliferation. Mutations leading to skipping of exon 14 (METΔex14) within the juxtamembrane domain of MET impair receptor degradation and prolong oncogenic signaling, contributing significantly to tumor progression across multiple cancer types. METΔex14 mutations are associated with aggressive clinical behavior, therapeutic resistance, and poor outcomes. Next-generation sequencing from both tissue and liquid biopsies has significantly improved the detection frequency of METΔex14 in lung and other cancers. However, clinical trials targeting METΔex14 have rendered partial responses and mixed outcomes due to the lack of a comprehensive mechanistic understanding of METΔex14 regulation and a diverse mutational landscape. This review synthesizes current knowledge on the mechanistic basis of METΔex14-driven oncogenesis, including alterations in receptor dynamics, downstream signaling perturbations, genomic alterations underlying this mutation, and mechanisms of acquired therapeutic resistance. We further discuss the clinical implications of these insights and highlight future research directions essential for optimizing targeted therapies.

Heart failure (HF) is a leading cause of death worldwide and the associated mortality and socioeconomic burden is predicted to worsen. Current therapies for HF focus on managing the causes and symptoms; however, these current treatment options are unable to reverse heart muscle degeneration, with heart transplantation the only cure. The ability to re-muscularise the heart represents a significant unmet clinical need. Although numerous biological pathways driving re-muscularisation have been identified, delivery of therapeutic factors is challenging. Modified mRNA (modRNA) is synthetic mRNA with greater gene packaging capacity, low immunogenic response and allows transient but robust protein expression. In this mini-review, we highlight the emerging discoveries surrounding the application of modRNA in the cardiovascular field. Specifically, we focus on different examples illustrating how modRNA delivery post-myocardial infarction can drive cardiomyocyte proliferation and achieve cardiac regeneration. In addition, we demonstrate how modRNA is being used for protein replacement and Cas delivery for both modelling and therapeutic studies focussed on genetic cardiac diseases. For these applications, in particular Cas delivery, the transient nature of modRNA overexpression is a beneficial property with reduced side effects compared with other modalities. Finally, we preview some of the roadblocks limiting the clinical translation of modRNA and avenues being explored to overcome these. In summary, the flexibility of modRNA combined with its improved safety profile provides a gene overexpression tool capable of integration into all steps of the preclinical and clinical therapeutic pipeline enabling the discovery of improved treatments for HF.

The maintenance of cell functions in response to various stimuli is fulfilled by tightly controlled homeostatic processes. The basoapical structure of normal epithelia is increasingly recognized as the guardian of homeostasis. It has recently been demonstrated that apical polarity, depicted by lateroapical tight junctions, is controlled by gap junctions and sets the resting membrane potential, itself essential for homeostasis, in the breast luminal epithelium. In the breast, the disruption of apical polarity is recognized as a necessary step toward cancer onset, which calls for a better understanding of its consequences on the mechanisms of homeostasis all the way to the genome. Here, we extend the traditional apical junctional complex to include gap junctions and investigate its relation with epigenetically- driven and higher order chromatin organization. The disruption of apical polarity affects different types of molecular networks that remodel chromatin with a tendency toward openness or relaxation, a status typically associated with instability and cancer onset. Events known to foster the development of cancers, such as chronic inflammation, oxidative stress, stiffer microenvironment, and aging, are all triggering the disruption of apical polarity, which leads us to explore possibilities to re-establish full polarity. Focusing on gap junction intercellular communication mediated by Connexin 43 might be an interesting therapeutic option for retinoic acid derivatives. However, in light of the different degrees of apical polarity loss, we surmise that the resulting chromatin alterations might depend on the way apical polarity is disrupted initially, which suggests that therapeutic combinations targeted also toward these alterations might be required.

Pluripotent stem cells (PSCs) possess the remarkable ability to self-renew and differentiate into nearly any cell type, making them invaluable for both research and therapeutic applications. Despite these powerful attributes, PSCs are vulnerable to genetic and epigenetic instabilities that can undermine their reliability and safety. While genetic abnormalities can be routinely monitored with established guidelines, epigenetic instabilities often go unchecked. Among the most recurrent epigenetic defects in PSCs are errors in genomic imprinting - a process that governs parent-of-origin-specific monoallelic expression of certain genes through differential marking of the two parental alleles by DNA methylation. When disrupted, it becomes a source of a dozen developmental conditions known as imprinting diseases. In PSCs, once imprinting errors arise, they remain throughout cellular differentiation, casting uncertainty over the use of PSC-derived cells for disease modelling and regenerative medicine. In this review, we provide an overview of imprinting defects in both mouse and human PSCs, delving into their origins and consequences. We also discuss potential correction strategies that aim to enhance imprinting stability, ultimately paving the way for safer, more reliable PSC use in research and clinical applications.

Protein kinases are master regulators of myriad processes in eukaryotic cells playing critical roles in growth, metabolism, cellular differentiation, and motility. A subclass of protein kinases is regulated by their ability to be localized and activated by the phosphoinositide phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This includes multiple members of the AGC and TEC family kinases, which contain PIP3 binding pleckstrin homology (PH) domains. It has been postulated that they can be activated by PIP3-mediated disruption of autoinhibitory interactions between their kinase domains and PH domains. There has been considerable controversy based on differing molecular models for how these kinases are regulated by lipid binding and post-translational modifications. This review focuses on understanding the molecular underpinnings for how the PH domains of these enzymes regulate kinase activity and what role PIP3 plays in pathway activation. A specific focus is on the integration of experimental data derived from X-ray crystallography, cryo-electron microscopy, and hydrogen deuterium exchange mass spectrometry along with recent advances in artifical intelligence enabled protein modeling. The main lipid-binding enzymes described are the AGC protein kinases 3-phosphoinositide-dependent kinase (PDK1) and Akt, and the TEC family kinase, Bruton’s agammaglobulinemia tyrosine kinase (BTK).