Small protein B (SmpB) is a key regulator of trans-translation in bacteria. The interactome of Mycobacterium tuberculosis (Mtb) ClpX revealed SmpB alongside multiple transcriptional regulators and σ factors that can alter the transcriptional profile. The finding that ClpX could also be identified in the Mtb SmpB interactome suggested both physical and functional linkages between trans-translation and targeted protein degradation. The trans-translation mechanism facilitates the release of stalled ribosomes and the attachment of ssrA degron sequences to aberrant proteins. We show that both SmpB and the previously described Mtb ClpX adaptor, single-stranded DNA binding protein (SSB), bind to the N-terminal domain of ClpX. However, unlike the adaptor SSB, SmpB binding does not enhance ClpX ATPase activity. Interaction studies using a model substrate with an exposed ssrA degron revealed that SmpB enhances ClpX-substrate interactions. ClpX unfoldase activity, on the other hand, enables targeted degradation of proteins containing the ssrA degron. ClpX also facilitates the release of specific σ factors from inactive σ/anti-σ complexes by degrading anti-σ factors containing the ssrA degron, thus indirectly influencing the transcription profile. Together, these observations suggest that SmpB and ClpX interactions and interacting protein networks exert both direct and indirect effects on the Mtb transcriptional profile.

Molecular mechanisms of quercetin in regulating antioxidant defense and pyroptosis pathways in the redclaw crayfish (Cherax quadricarinatus).

Elymus nutans transcription factor EnWRKY41 negatively regulates Arabidopsis thaliana drought tolerance by reducing callose deposition via EnGlu1.

Carbon catabolite repression in Gram-positive bacteria, including the recently developed insights.

Resistance of hepatocellular carcinoma (HCC) to sorafenib represents a major clinical challenge, involving complex metabolic alterations and epigenetic regulatory changes. However, the underlying mechanisms remain incompletely understood. In this study, we found that the level of histone H3 lysine 18 lactylation (H3K18la), derived from lactate, was significantly elevated in sorafenib-resistant HCC cells. Mechanistically, using Micrococcal Nuclease-Chromatin Immunoprecipitation-quantitative Polymerase Chain Reaction and related techniques, we demonstrated that H3K18la is directly enriched at the promoter region of homeobox B13 (HOXB13) and functions as a potent transcriptional activator to upregulate its expression. Further mechanistic investigations revealed that HOXB13 stabilizes hypoxia-inducible factor-1α (HIF-1α) protein expression, thereby activating the HIF-1 signaling pathway, promoting lipid metabolism reprogramming, and enhancing lipid accumulation. Functional experiments demonstrated that the inhibition of H3K18la or knockdown of HOXB13 effectively reversed lipid accumulation and significantly increased cellular sensitivity to sorafenib. This study systematically delineates a signaling cascade (the H3K18la-HOXB13-HIF-1 axis) spanning metabolites, epigenetic modifications, transcriptional regulation, and downstream metabolic phenotypes, thereby deepening our understanding of tumor drug resistance mechanisms and providing potential therapeutic targets for overcoming HCC resistance to sorafenib.

Ginsenoside Rb1 as a multi-target modulator in heart failure: Mechanistic insights into extracellular remodeling and transcriptional pathways from network pharmacology, molecular dynamics, and binding free energy analyses.

The posttranslational modification landscape of transcription factors in osteoblast differentiation and bone formation.

Genetic variants affecting the RNA polymerase II complex have been associated with various neurodevelopmental disorders (NDDs). SUPT6H, an RNA polymerase II-associated elongation factor and a histone chaperone, plays a critical role in transcriptional regulation. However, the contribution of SUPT6H variants to human NDDs and the phenotypic consequences of its loss-of-function in vivo remain unexplored. Here, we analyzed 18 published sporadic single-nucleotide variants (SNVs) of SUPT6H associated with human developmental disorders. Molecular modeling suggests that these variants are likely deleterious, leading to loss of function. Consistent with this, homozygous or heterozygous Supt6 null mice exhibit embryonic lethality, underscoring its essential role during development. To investigate the postnatal consequences of Supt6 deficiency, we generated conditional Supt6 knockout (KO) mice with targeted deletion in parvalbumin-expressing GABAergic interneurons (cKOPV). Homozygous Supt6 cKOPV mice displayed motor defects and behavioral seizures, whereas heterozygous counterparts exhibited behavioral phenotypes relevant to neuropsychiatric disorders despite normal motor activity. Notably, both heterozygous and homozygous Supt6 cKOPV mice showed a significant reduction in parvalbumin-expressing neurons compared to wild-type controls. These findings establish a direct link between Supt6 loss-of-function and neurodevelopmental phenotypes, highlighting its critical role in maintaining interneuron populations and neural circuit integrity. Altogether, our results suggest that deleterious SUPT6H variants may contribute to the etiology of NDDs, providing valuable insights into its function and potential as a therapeutic target.

Network analysis to understand gene regulation: across spatial scales and toward multi-level models.

Identification and functional study of CDK gene family in cell proliferation in the Chinese mitten crab (Eriocheirsinensis).

Deciphering cis-regulatory regions in genomes is essential for understanding various physiological processes and pathological mechanisms. Regulatory signatures, namely promoter motifs, transcription factor binding sites, enhancers, GC content, CpG islands, DNA structural motifs, and other cis-regulatory features, are well-established for their roles in transcriptional regulation. However, these features often exhibit species-specific variations, challenging the identification of conserved regulatory principles across different genomes. In this study, we introduce DNA sequence perplexity as an innovative and efficient information-theoretic metric for characterizing cis-regulatory regions. Derived from information theory and natural language processing, perplexity quantifies the complexity and predictability of sequence, offering a motif-independent framework for DNA analysis. By examining transcription and translation start site regions across 1180 species spanning diverse taxa, we demonstrate that cis-regulatory regions consistently exhibit lower perplexity compared to adjacent flanking regions. This trend persists irrespective of taxonomic classification, establishing perplexity as an evolutionarily conserved pattern of regulatory DNA. Additionally, we observe an inverse correlation between perplexity and promoter strength in yeast datasets, suggesting that higher transcriptional outputs are associated with markedly reduced sequence perplexity. Our findings reveal that perplexity may hold valuable insights into the generalizable aspects of cis-regulatory DNA architecture. Integrating this abstraction-based strategy with motif-based approaches and high-throughput functional datasets could enhance its applicability in predictive applications across comparative and functional genomics.

Insights on the microbial resistance mechanisms of Listeria monocytogenes to Pulsed Electric Fields (PEF) treatments.

CRMIPred: Identifying the spatial interactions among cis-regulatory modules via considering their cross-attended epigenetic profiles.

Comparative genomics of Idotea balthica populations: Evolutionary divergence between Mediterranean and Baltic lineages.

Unveiling the multifaceted roles of crop secondary metabolites: From quality enhancement and stress resilience to molecular regulation and precision improvement.

The voltage-gated potassium channel KV1.3 (KCNA3) is a critical ion channel regulating membrane potential in immune cells, facilitating sustained calcium influx and activating downstream signaling events. Besides its canonical role as an ion channel, KV1.3 has been postulated to exert additional functions in immune biology. In this review, we summarize how recruitment of KV1.3 into cholesterol-rich lipid raft microdomains positions KV1.3 as a scaffold (demonstrated directly in T cells and microglia) for kinases, adaptor proteins, and transcriptional regulators, integrating ion flux with receptor signaling pathways that control adhesion, migration, and damage-associated molecular patternrelease in immune cells. We further discuss how these observations may explain recent findings in KV1.3 function in neutrophil biology and how its inhibition may offer a refined strategy to selectively modulate immune responses in sterile inflammation and beyond. This highlights the need for neutrophil-specific KV1.3 interactomics and spatiotemporal raft/adhesion nanodomain mapping.

Phosphate (Pi) is an essential nutrient for plant growth, and understanding how Arabidopsis thaliana root cells respond to Pi deficiency is crucial to decipher whole plant responses. We perform high-resolution transcriptomic profiling across five distinct root cell types, identifying differentially expressed genes (DEGs) and differential alternative splicing (DAS) events that define cell-type-specific Pi-responsive regulatory layers. We identify over 7000 DEGs and 733 DAS that act largely independently and are cell-type-specific, affecting distinct loci and biological pathways. Transcription factors such as LHY, REV7 and MYB88, linked to circadian rhythms, stomatal regulation and ABA perception, acquire novel functions under Pi starvation. We show that the splicing factor SR45, previously associated with iron homeostasis, regulates Pi allocation. The sr45-1 mutant displays increased root-to-shoot Pi ratio and reduced biomass. A substantial number of Pi-responsive DAS transcripts are SR45 bound, indicating that SR45 operates as a regulatory hub for Pi transport and homeostasis. This cell-type-resolved dataset provides a detailed molecular map of Pi deficiency responses and highlights the importance of post-transcriptional regulation in shaping root adaptive strategies. Transcriptional regulation and alternative splicing emerge as coordinated mechanisms orchestrating plant adaptation to Pi starvation.

In silico discovery and biological evaluation of a novel selective HDAC8 inhibitor featuring 1H-pyrazolo[3,4-b]pyridine scaffold.

In this issue, Wang et al. (https://doi.org/10.1083/jcb.202509044) report that in the syncytial fungus Neurospora crassa, the core proteins regulating circadian rhythms are shared between adjacent nuclei. They also show that core circadian proteins form highly dynamic nuclear bodies that oscillate in both abundance and colocalization, indicating potential for switch-like spatiotemporal regulation of circadian transcription.

Tributyltin (TBT) is a widespread marine contaminant that affects the development and reproduction of marine invertebrates; however, its molecular impacts on early embryonic development remain poorly understood. In this study, we investigated the effects of environmental concentrations of TBT on the miRNA expression profiles of the marine gastropod Tritia mutabilis during intracapsular embryogenesis. Embryos were exposed for 10days to low (10-12M) and high (10-10M) concentrations of TBT, and the differential expression of miRNAs was assessed by high-throughput sequencing. Obtained results revealed a significant modulation of several miRNAs across treatments, with a set of 11 miRNAs responding to both low and high TBT concentrations, while miR-486-5p and miR-183-5p were specifically modulated under the low TBT concentration, and miR-263b, miR-184, and miR-100-5p were exclusive to the highest concentration. Pathway analyses identified a range of biological processes affected, including nervous system development, cellular functions such as proliferation and cell growth, signal transduction, cellular component assembly and cell-cell interactions. Notably, several pathways were highly enriched (i.e., ≥100 regulated target genes) under both conditions, including focal adhesion, Ras signaling, regulation of actin cytoskeleton, Rap1 signaling, cAMP signaling, calcium signaling, and cGMP-PKG signaling pathways, highlighting the vulnerability of developmental and cellular communication networks, and further supported by the expression analysis of the corresponding miRNA-regulated target genes. These findings demonstrate that TBT contributes to the developmental abnormalities of marine gastropod embryos by modulating miRNA-mediated control of gene transcription. Our results contribute to advancing the understanding of miRNAs' potential utility as biomarkers for environmental monitoring.