Rapid advances in high-throughput technologies and computational tools have ushered in a transformative era for scientific discovery. However, the acceleration of data generation has outpaced our conceptual frameworks for interpreting it. By examining current challenges in drug discovery, phenotypic screening, and model transferability, I argue that the future of scientific integrity depends on our ability to balance technical proficiency with the classical principles of hypothesis negation. Because the scientists who interpret data are themselves prone to bias and error, these safeguards must apply to human judgment as rigorously as to computational tools. I also confront a central tension: the mechanistic understanding I advocate may not scale to systems of cellular complexity. Finally, I propose a collaborative training approach that sustains both experimental excellence and theoretical depth. Each challenge maps onto the Data-Information-Knowledge-Wisdom (DIKW) hierarchy: failures at the D→I transition (underdetermined models), at I→K (undefined null hypotheses and black-box modeling), at K→W (non-transferable animal models and cross-domain blindness), or in the collapse of the entire chain when paradigm inertia forecloses the revision that wisdom demands.
The study shows that interpretation of H3K4me3 is essential for translating chromatin information into the developmental decisions that establish embryonic patterning in Arabidopsis . Development of multicellular organisms requires the precise coordination of gene expression programs. Whereas histone modifications are key regulators of transcriptional states, how these modifications are interpreted during early development remains poorly understood. Here, we investigate the role of H3K4me3 recognition during embryogenesis in Arabidopsis thaliana . We identify ALFIN-LIKE (AL) proteins as essential H3K4me3 readers required for early seed development. Loss of AL function leads to severe defects in embryogenesis, including impaired asymmetric zygotic division, disrupted patterning, and loss of lineage restriction. At the molecular level, AL deficiency results in widespread transcriptional misregulation and is associated with local changes in chromatin state, including reduced H3K4me3 and a concomitant increase in H3K27me3 at a subset of loci, including key developmental and flowering-time regulators. Together, our results show that interpretation of H3K4me3 by AL proteins is required for proper gene expression during early development and reveal a context-dependent relationship between activating and repressive chromatin states, highlighting a role for H3K4me3 in shaping gene expression during plant embryogenesis.
Gut microbiota and its metabolites shape MASLD progression by modulating intestinal barrier integrity, inflammation, metabolism, and liver signaling. The gut–liver axis is an important regulator of homeostasis, and its dysregulation has been implicated in the pathogenesis of metabolic dysfunction–associated steatotic liver disease (MASLD). In this review, we summarize current knowledge on both compositional alterations of the gut microbiome in MASLD and the functional consequences of these changes. We first discuss changes across major microbial domains, including bacteria, archaea, eukaryota, and bacteriophages, and then focus on microbiota-derived metabolites, such as short-chain fatty acids, trimethylamine and its derivative trimethylamine N-oxide, tryptophan-derived indoles, secondary bile acids, and other bioactive compounds. Their complex impacts on intestinal barrier integrity, inflammation, lipid and glucose metabolism, and immune and hormonal signaling in the liver are highlighted. We further examine mechanisms involving the translocation of microbial products and the modulation of nuclear and membrane receptors. Finally, we outline current challenges and knowledge gaps that need to be addressed to better understand the role of the gut microbiota in MASLD. Graphical Abstract lsa;10/1/e202603756/GA F1 GA
Recombination-related factors are linked to gene-body Pol II occupancy and transcription-associated chromatin states at highly active genes in yeast. Transcription by RNA polymerase II (Pol II) must be tightly regulated to maintain gene expression homeostasis, yet how Pol II occupancy is shaped at highly active genes remains incompletely understood. Here, we examine the relationship between the homologous recombination–related factors Esc2 and Rad57 and Pol II distribution in budding yeast. Genome-wide analyses reveal that Esc2 and Rad57 preferentially associate with the gene bodies of highly transcribed housekeeping genes and are linked to a chromatin context that also includes the protein phosphatase Sit4 and its cofactor Rrd1. Loss of Esc2 and Rad57 is accompanied by increased Pol II occupancy within gene bodies, whereas the effect on steady-state RNA abundance is selective rather than uniform. Under the tested anchor-away conditions, acute Rad57 depletion in an esc2 Δ background did not fully recapitulate the broader transcriptome imbalance and impaired growth observed after chronic Esc2/Rad57 loss. Together, our findings reveal an association between recombination-related factors and gene-body Pol II occupancy and suggest that Esc2/Rad57 loss is linked to transcription-associated chromatin changes in yeast.
SARS-CoV-2 nucleocapsid promotes recruitment of IRF and AP-1 transcription factors, RNA polymerase II, and the elongation factor eEF1A1 to promoters of pro-inflammatory genes, revealing a previously unrecognized nuclear role for eEF1A1. SARS-CoV-2 variants display substantial genetic and phenotypic diversity, yet the molecular mechanisms underlying their effects on host gene regulation need further investigation. We performed a transcriptomic analysis of host responses to multiple SARS-CoV-2 variants, including Delta and Omicron. Despite their divergence, all variants induced a conserved transcriptional program in human lung epithelial cells characterized by activation of interferon regulatory factors (IRFs), immediate–early genes, and downstream cytokines. We identify the viral nucleocapsid (N) protein as a central driver of this transcriptional reprogramming, as N expression alone partially recapitulated the host response to infection. Mechanistically, N promotes recruitment of interferon regulatory factors and AP-1 transcription factors, RNA polymerase II, and the elongation factor eEF1A1 to promoters of pro-inflammatory genes, revealing a previously unrecognized nuclear role for eEF1A1. Disruption of the N-eEF1A1 interaction, genetically or pharmacologically using the eEF1A interactant plitidepsin, abolished transcriptional complex formation and reversed host gene dysregulation, identifying a conserved host–virus regulatory axis and potential pan-variant therapeutic target.
