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At least 19 recordsLinked to original sources

PubMed2025

Re-arranging the Cis-regulatory Modules of Hox Complex in Drosophila via FLP-FRT and CRISPR/Cas9.

FLP-FRT, a well-established technique for genome manipulation, and the revolutionary CRISPR/Cas9, known for its targeted indels, are combined in a novel approach. This unique method is applied to the Hox genes in the Drosophila melanogaster bithorax complex, which are closely located to the cis-regulatory modules that define their spatial-temporal regulation. The number and position of these genes are directly correlated to their expression pattern. This chapter unveils the exciting potential of this combinatorial use of FLP-FRT and CRISPR-Cas9 to rearrange the cis-regulatory modules of the Hox complex in Drosophila melanogaster.

Animals↗

PubMed2025

The SlGRAS9-SlMYC1 regulatory module controls glandular trichome formation and modulates resilience to pest in tomato.

Trichomes of aerial plant organs contribute to adaptive responses to abiotic and biotic stresses. In horticultural plants, increasing glandular trichome density is an effective breeding strategy to enhance resistance to herbivores through promoting the capacity to produce specialized metabolites. The regulatory mechanisms controlling multicellular trichome formation are only partially understood. In this study, we reveal that SlGRAS9 and SlMYC1 transcription factors form a regulatory module controlling glandular trichome formation in multiple tissues. Knockout of SlGRAS9 or overexpression of SlMYC1 in tomato leads to an increased number of type VI glandular trichomes and to higher terpenoid accumulation in leaves, petals, sepals, and fruits. Conversely, knockout of SlMYC1 results in reduced type VI glandular trichomes number and terpenoid levels. Promoter-binding and genetic interaction experiments revealed that SlGRAS9 negatively regulates the transcription of SlMYC1, indicating that the regulation of glandular trichome formation by SlGRAS9 is dependent, at least partly, on SlMYC1. Consistently, both SlGRAS9 knockout and SlMYC1 overexpression result in higher tolerance of tomato plants to spider mites and aphids. In addition to adding some of the missing components to the mechanisms controlling formation of type VI glandular trichome, our findings also uncover new targets for breeding strategies aimed at improving crop protection against pest invasion, thus ensuring crop yield resilience to climate change.

Trichomes↗

PubMed2025

A Simple Method to Analyze Context- and Tissue-Specific Cis-Regulatory Modulations of Homeotic (HOX) Genes Using ChIP.

Homeobox genes (HOX), the master regulators, deploy a unique set of target genes to coordinate and orchestrate the spatiotemporal development of an organism. HOX encoded transcriptional factors regulate the expression of target genes by binding to the specific sequences on the genome. Chromatin Immunoprecipitation (ChIP) and Chromatin Immunoprecipitation with Sequencing (ChIP-Seq) are widely used to map and understand specific gene locus and global regulatory regions on the genome. ChIP is a powerful technique of cross-linking the proteins bound to the DNA, fragmenting DNA to the desired size, and pulling them down using specific antibodies to enrich and analyze the protein-bound DNA. Based on the mapping information, a differential ChIP can be performed to understand cis-regulatory modulations at a defined locus by two developmental stages. This chapter describes the differential ChIP used to identify new targets by comparing two different developmental stages simultaneously using Drosophila melanogaster.

Animals↗

PubMed2026

A CsWRKY46-CsPBL9-CsARI1 tripartite regulatory module coordinates H2O2 production and callose deposition in citrus fruit immunity.

Plant immunity against pathogens involves multiple immune responses and intricate regulatory networks. However, how immune networks are deployed in fruit remains poorly understood. Here, we show that citrus fruit immune responses, including hydrogen peroxide (H2O2) production and callose deposition, are multiply regulated by transcriptional activation, phosphorylation, and ubiquitination. Citrus sinensis genes encoding nicotinamide adenine dinucleotide phosphate (NADPH) oxidase CsRBOHG and callose synthase CsCalS5, responsible for H2O2 production and callose deposition, respectively, are transcriptionally activated by CsWRKY46. Phosphorylation-enhanced activity of CsRBOHG by CsPBL9 enhances immunity. RING1-IBR-RING2 (RBR)-type E3 ligase CsARI1, acting as an immune brake, ubiquitinates CsRBOHG and CsCalS5 for degradation. Interestingly, CsARI1 also shows a moonlight function wherein it interacts with CsPBL9 in a non-ubiquitination manner, disrupting CsPBL9's interaction with CsRBOHG. This CsARI1-CsPBL9 interaction is stimulated by H2O2 as feedback. Moreover, H2O2 contributes to callose deposition, indicating an interplay between two immune responses. Our study reveals a tripartite regulatory hub orchestrating self-linked immunity in citrus fruit.

CP: plants↗

PubMed2026

A CqbZIP55-CqPIF3 regulatory module associated with light-responsive flavonoid biosynthesis during quinoa seedling de-etiolation.

Quinoa (Chenopodium quinoa) is an emerging leafy vegetable and microgreen crop rich in health-promoting flavonoids, yet the regulatory mechanisms linking light perception to early metabolic adaptation remain unclear. Here, we integrated phenotypic, transcriptomic, metabolomic, and molecular analyses to investigate early de-etiolation responses in quinoa seedlings. Short-term light exposure rapidly promoted seedling establishment and induced transcriptional programs associated with photosynthesis, carbon metabolism, hormone signaling, and flavonoid biosynthetic gene expression, whereas metabolite changes were more limited, indicating temporal uncoupling between transcriptional activation and metabolic accumulation. Genome-wide bZIP analysis identified CqbZIP55 as a light-responsive regulator that directly binds and activates the CqCHS promoter. CqPIF3 also bound the CqCHS promoter and showed stronger transactivation activity than CqbZIP55 in transient reporter assays. Protein interaction and dual-luciferase assays showed that CqbZIP55 physically interacts with CqPIF3 and modulates CqPIF3-associated promoter activity. Exogenous quercetin upregulated CqbZIP55 and prolonged CqCHS expression, suggesting a candidate metabolite-associated reinforcement mechanism. Together, these findings support functional interplay between CqbZIP55 and CqPIF3 in light-responsive regulation of flavonoid biosynthetic gene expression in quinoa seedlings, while further quinoa-based perturbation and in vivo promoter-occupancy assays are required to establish their physiological role in planta. This study provides a framework for further investigation of photoprotective metabolic regulation in quinoa.

Chenopodium quinoa↗

PubMed2026

Genome-wide identification of the carotenoid cleavage dioxygenase gene family in wheat and analysis of the TaDREB-7A-TaNCED9a regulatory module conferring drought tolerance.

Carotenoid cleavage dioxygenases (CCDs) play critical roles in plant growth, development, and abiotic stress responses, yet their genome-wide identification and drought response mechanisms remain unexplored in wheat. In this study, 34 TaCCD genes were identified in wheat, distributed across 15 chromosomes and phylogenetically classified into five subfamilies. Gene structure analysis indicated that members within each subfamily shared conserved motifs and similar intron-exon arrangements. Cis-regulatory element analysis suggested the potential roles of these genes in stress adaptation, developmental processes, and hormone signaling. Moreover, prediction of tertiary structures and protein-protein interactions revealed unique structural features and potential interacting partners of the TaCCD proteins. In addition, TaNCED9a, a member of the TaCCD family, showed the highest transcript level in wheat roots among all detected TaCCD genes and was significantly induced by drought stress. Subcellular localization assay indicated that TaNCED9a was located in chloroplasts. Downregulation of TaNCED9a expression led to reduced drought resistance in wheat, accompanied by an accumulation of reactive oxygen species and a decrease in endogenous abscisic acid levels. Using yeast one-hybrid, dual-luciferase, and tobacco transient co-expression assays, the upstream regulatory factor TaDREB-7A was identified, which can regulate the expression of TaNCED9a. Additionally, a KASP molecular marker was developed to identify the superior haplotype TaNCED9a-HapI, which exhibited a significantly higher germination rate compared to TaNCED9a-HapII under drought conditions, and was predominant in wheat. These results offer valuable insights into the TaCCD gene family's response mechanisms to drought stress in wheat, simultaneously identifying promising genetic resources for enhancing drought tolerance through molecular breeding.

CCD↗

PubMed2026

Beyond the CO-FT regulatory module: E1 and PHYA emerge as players in photoperiodic regulation of flowering in legumes.

The legume family (Fabaceae) is the third largest in plants and includes several crop species that are able to fix nitrogen, promote soil health, and contribute to food security worldwide. Recent progress in legume genetics and genomics allowed the identification of photoperiod-dependent flowering loci, which were incorporated into specific signalling networks. Functional characterization of these regulators revealed new roles for known photoreceptors such as phytochrome A, and it also identified legume-specific B3 domain transcriptional factors (E1 and E1-like proteins). This suggests some diversification from the traditional CONSTANS-FLOWERING LOCUS T module present in other angiosperms. Although most of the findings discussed herein pertain to species from the two main legume clades, the Galegoids (e.g. alfalfa, clover, and pea) and the Phaseoloids (e.g. common bean, soybean, cowpea, and pigeon pea), research on flowering regulation in the basal Genistoid clade (e.g. lupins) will also be addressed. We propose that functional diversification of photoperiod-dependent flowering strategies in the different legume species could have contributed to their environmental adaptation and allowed their geographical expansion and success worldwide.

Photoperiod↗

PubMed2026

A cooperative regulatory module between TAGL2 and JMJC1 activates specific defense genes against root-knot nematodes in tomato.

Plant-parasitic nematodes (PPNs) threaten global food security. Although epigenetic modifications are crucial for plant immunity, how histone modifiers contribute to root-knot nematodes (RKNs, Meloidogyne incognita) resistance remains unclear. Here, using genetic, molecular and biochemical approaches, we investigated the epigenetic and transcriptional mechanisms underlying RKN resistance mediated by the histone demethylase (HDM) JMJC1 and the MADS-box transcription factor TAGL2 in tomato (Solanum lycopersicum). We identified JMJC1 as an RKN-induced positive defense regulator targeting H3K9me3 and H3K27me3 histone marks. JMJC1 physically interacts with TAGL2, which also positively regulates RKN resistance. Transcriptomic analysis indicated that TAGL2 regulates multiple layers of the plant defense network, transcriptionally activating representative genes from distinct pathways (including PUB10, bHLH98, CCaMK, and SAUR3), which we validated as positive regulators of RKN resistance via virus-induced gene silencing (VIGS). At the chromatin level, TAGL2 and JMJC1 co-regulate these loci, associating with localized H3K9me3 and H3K27me3 reduction. Furthermore, TAGL2 directly activates JMJC1 transcription, establishing a positive feedback loop that amplifies immune signaling. Our findings reveal a cooperative model wherein a HDM and a transcription factor coordinate at specific loci to fine-tune multiple defense layers at both epigenetic and transcriptional levels, providing insights for breeding durable nematode-resistant plants.

Solanum lycopersicum↗

PubMed1976

Modulation of regulatory mechanisms operative in the cyclical production of antibody.

Modulation of the cyclical response in rabbits to aggregated human gamma globulin (AHuIgG) was investigated in order to study some of the parameters involved in self-regulation of the immune response. Several mitogens (lipopolysaccharide [LPS], phytohemagglutinin [PHA], and concanavalin A [Con A]), when injected simultaneously with antigen, have been shown to modulate the normal splenic plaque-forming cell (PFC) response in rabbits to a single intravenous injection of AHuIgG. This response to AHuIgG has previously been characterized by the initial appearance of PFC in the spleen 3 days later, with a peak of PFC at 5 days after injection. The number of PFC in the spleen then decreases and remains at a low level until a second increase begins on day 10, peaking on day 13. The 8-day cycle between peak PFC repeats, with a third peak appearing on day 21. In the present studies, injection of LPS with AHuIgG was shown to affect the PFC response by enhancing only the initial peak of PFC, PHA was shown to enhance both the initial and secondary peaks of PFC, while injection of Con A with AHuIgG resulted in a prolonged increase in PFC with no apparent cycling. Irradiation 24 h after injection of antigen resulted in PFC kinetics similar to those observed with PHA, although the increase in PFC was more marked with irradiation. Thus, although LPS, PHA, Con A, and irradiation markedly affected the immune response to AHuIgG, Con A was the only substance which altered the cyclical appearance of PFC to HuIgG. The cyclical nature of the PFC kinetics was shown to occur with either intravenous or intraperitoneal injection of antigen and in both primary and secondary responses, provided that the rabbits were primed with a low dose of antigen. Data were obtained that suggest that the response in distal lymph nodes may be regulated by immunological events occurring in the spleen. Cycling of PFC was not observed in the draining node after subcutaneous injection of AHuIgG in the hind foot. However, if the antigen was also injected intravenously at the same time as the subcutaneous injection, the response in the node became cyclical.

Animals↗

PubMed2025

Multi-omics reveals an ecdysone-activated Eip75B-FABP signaling axis coordinating nutrient metabolism for development in Hermetia illucens.

INTRODUCTION: Efficient nutrient storage is essential for insect development and energy homeostasis; however, the mechanisms coordinating nutrient allocation during ontogeny are not well understood. Elucidating these systems may yield valuable insights to insect metabolic adaptation. OBJECTIVES: This study aimed to identify regulatory modules governing nutrient metabolism in insects, focusing on hormonal and metabolic interplay. METHODS: Multi-omics profiling (proteomics, phosphoproteomics, and transcriptomics) was conducted throughout the life cycle, from egg to adult, to identify metabolic regulators. RNAi was utilized for gene knockdown, followed by qRT-PCR and mitochondrial DNA quantification to evaluate knockdown efficiency and its metabolic implications. Assessments of nutrient metabolism were performed using assays for triglycerides, crude protein, and fatty acid synthase. EMSA and BODIPY staining examined transcriptional regulation and lipid droplet dynamics. RESULTS: Utilizing an integrative multi-omics approach, this study elucidates the temporal metabolic regulators in insects. A conserved regulatory module was identified in which the PPAR homolog, ecdysone-induced protein 75B (Eip75B), functions as a transcriptional activator of fatty acid binding protein (FABP), sustaining lipid metabolic homeostasis during the larval stage. PPARγ modulators (rosiglitazone and GW9662) alter lipid accumulation, along with the expression of Eip75B and FABP, which was measured by qRT-PCR. Furthermore, the deficiency of FABP may reprogram metabolic pathways by inhibiting lipid storage and promoting mitochondrial β-oxidation, as supported by increased mitochondrial DNA copy number, as well as enhancing protein synthesis. This metabolic change could be modulated by ecdysone signaling, as hormonal supplementation effectively rescued the lipid loss phenotype. Our results establish the ecdysone-Eip75B-FABP signaling axis as a central regulatory module that integrates hormonal and nutrient-sensing signals to control insect nutritional metabolism. CONCLUSION: The ecdysone-Eip75B-FABP axis integrates hormonal and nutrient signals to regulate metabolic plasticity, underscoring a universal strategy for developmental energy allocation. The data also offer potential implications for research on metabolic disorders and bioenergy applications.

Animals↗

PubMed2026

Natural variation in the PmbHLH162 promoter regulates anthocyanin biosynthesis and accumulation in Prunus mume.

Anthocyanin accumulation is a vital agronomic and ornamental trait, as it not only contributes to adaptation to environmental stress but also enhances ornamental value. In this study, a genome-wide association study (GWAS) was conducted using 328 accessions of mei (Prunus mume) to identify single-nucleotide polymorphisms (SNPs) associated with red pigmentation in petals, filaments, and xylem. Based on these significant SNPs, we defined 2 haplotypes (bHLH162hap1 and bHLH162hap2) and identified PmbHLH162, a bHLH transcription factor gene responsible for anthocyanin biosynthesis regulation. Transient silencing of PmbHLH162 in mei petals via Agrobacterium-mediated transformation resulted in significant color fading, whereas its overexpression dramatically elevated anthocyanin levels. Haplotype analysis showed that 2 promoter variants in bHLH162hap2 (Chr03_2669885 A/C and Chr03_2670272 A/G) alter the binding affinity of transcription factors PmWRKY18 and PmWRKY70. Stronger binding to the G/C alleles gave rise to higher PmbHLH162 expression in bHLH162hap2, thereby promoted red pigmentation in multiple tissues. By contrast, accessions carrying bHLH162hap1 displayed light/colorless phenotype without accumulation of red pigment. Furthermore, PmbHLH162 interacted respectively with PmMYC2, PmTT8, and PmEGL1 to form heterodimers, and markedly enhanced PmMYC2-mediated transcriptional activation of the anthocyanin biosynthetic structural genes PmCHS and PmANS. Geographic haplotype analysis revealed that bHLH162hap2 was predominantly enriched in high-latitude northern populations but was declining markedly at lower latitudes. Collectively, our study reveals the genetic and molecular basis underlying anthocyanin accumulation in mei and identifies a PmbHLH162-PmMYC2 regulatory module in which PmbHLH162 enhances PmMYC2-mediated activation of key anthocyanin biosynthetic genes. The additional interactions of PmbHLH162 with the MBW-associated bHLH factors PmTT8 and PmEGL1 further suggest potential crosstalk between this module and the canonical anthocyanin regulatory network.

Anthocyanins↗

PubMed2026

Noncoding transcription controls the developmental dynamics of long-range gene regulation.

The genomic regions regulating gene expression are often themselves transcribed into a variety of noncoding RNAs (ncRNAs). However, the regulatory roles of this noncoding transcription remain largely unknown. By using live imaging, we reveal that the sequential transcription of ncRNAs emanating from distinct regulatory elements underlies gene activation in Drosophila embryos. Single-allele co-visualization uncovers that optimal gene activation is achieved by only moderate levels of enhancer activity. Disrupting enhancer-associated ncRNAs causes precocious gene activation, providing evidence that ncRNAs control the timing of gene expression in development. We further show that enhancer transcription can regulate long-range interactions within complex regulatory landscapes. We propose that ncRNAs locally modulate regulatory element activity in cis to shape genome organization and orchestrate the temporal control of gene expression in development.

Journal Article↗

PubMed2026

Integrated analysis of ATAC-seq and RNA-seq reveals the TCP-ARF molecular module related to pathogenic process of phytoplasma infection in Paulownia fortunei.

BACKGROUND: Witches’ broom is an important disease of the Paulownia fortunei. Understanding the pathogenesis of witches’ broom is a prerequisite for its prevention and control. Phytoplasma is the pathogen of Paulownia witches’ broom. RESULTS: We investigated the changes in chromatin accessibility before and after phytoplasma infection in Paulownia fortunei by analyzing the DNA accessibility (ATAC-seq). In phytoplasma-infected P. fortunei (PFI) compared to healthy samples (PF), the closed regions of chromatin(1187 regions) were three times more than the open regions (352 regions). Fifty one percent of the accessible chromatin regions were overlapped with either H3K27ac or H3K9ac peaks. The closed regions were enriched in the conserved motif TGGGC[CT] that is recognized by the TCP transcription factor family. The closed regions in PFI are intersected with ARF family gene locus. The gene PfARF3 was verified to interact with the PfTCP23 transcription factor. The PfTCP23 was predicted to be interacted with the effector pawb44 in the pathogen of phytoplasma. CONCLUSIONS: The phytoplasma infection in P. fortunei is involved in the chromatin changes of the DNA accessibility and histone modification. The binding regions of TCP23 were found to be changed mostly in the accessibility between PFI and PF. The TCP-ARF module was found to be the possible regulatory module inducing the crinkled leaf trait.

RNA-Seq↗

PubMed2026

Light regulates capsaicinoid biosynthesis via the CaHY5-CaBBX2-CaACS8 module in pepper.

Capsaicinoids are a class of unique alkaloids that confer the pungent taste to pepper fruits. However, it remains largely unknown how light regulates the biosynthesis of capsaicinoids. We conducted a metabolic analysis on light- and dark-adapted pepper fruits. The results showed that dark-adapted pepper fruits had lower capsaicinoid contents and correspondingly downregulated transcription of capsaicinoid biosynthetic genes (CBGs), indicating that light plays a crucial role in capsaicinoid biosynthesis. Furthermore, silencing of CaHY5, a pivotal transcription factor gene in the light signaling pathway, decreased the content of capsaicinoid and suppressed the expression of CBGs, whereas transient overexpression of CaHY5 generated exactly opposite results. CaHY5 can bind to the G-box motif in the promoters of CaBBX2 and CaACS8, thereby enhancing their transcriptional levels. The activated CaBBX2 then binds to the T/G-box in the CaACS8 promoter to stimulate its expression. CaBBX2 or CaACS8 silencing led to decreased levels of capsaicinoids, while their transient overexpression produced increased capsaicinoid contents. Collectively, our results indicated that the light-activated CaHY5-CaBBX2-CaACS8 regulatory module plays a pivotal role in capsaicinoid biosynthesis. These findings provide new insights into the influence of light on capsaicinoid biosynthesis and potential targets for activation of this biosynthetic pathway in pepper.

Capsicum↗

PubMed2025

Foxi2 and Sox3 are master regulators controlling ectoderm germ layer specification.

In vertebrates, germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus. Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomics analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification.

Ep300↗

PubMed2025

Transposable Element-Mediated Cis-Regulation Drives the Evolution of dmrt1 as a Candidate Master Sex-Determining Gene in Black Carp.

Sex determination in vertebrates exhibits remarkable evolutionary plasticity, with diverse mechanisms and master sex-determining (MSD) genes arising independently across lineages. Among these, dmrt1, a dosage-sensitive gene, has repeatedly been recruited as an MSD gene through gene duplication or allelic diversification. However, the biochemical basis of such evolutionary transitions, particularly those driven by allelic diversification, remains largely unexplored. Here, we generated haplotype-resolved genome assemblies for both XX and XY black carp (Mylopharyngodon piceus) and identified a ∼40-kb region on chromosome 4, containing only dmrt1, as the candidate sex-determining locus. We discovered two Y-specific insertions in the dmrt1 promoter: a 13.4-kb highly repetitive element and an 11-bp motif. Functional assays revealed that these insertions act as enhancer and a promoter element, respectively, driving early, allele-specific upregulation of dmrt1 prior to gonadal differentiation. Notably, the 13.4-kb insertion contains transposable elements (TEs) functioning as cis-regulatory modules with transcription factor binding sites that mediate Y-specific activation. Our findings reveal a TE-mediated regulatory innovation that promoted dmrt1's evolution as a male-determining gene via allelic diversification, providing new insights into how mobile genetic elements drive the origin and diversification of sex-determining systems in vertebrates.

Animals↗

PubMed2026

A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.

Lineage-defining transcription factors are key oncogenic drivers but remain difficult to target pharmacologically due to the absence of ligandable pockets. The molecular rules governing substrate recognition by large HECT ubiquitin ligases also remain incompletely understood, limiting efforts to exploit these enzymes for targeted protein degradation. Here we combine genome-wide CRISPR knockout screening with base editor tiling screens at amino acid resolution, both coupled to an endogenous knock-in reporter of the SCLC lineage oncogenic transcription factor ASCL1, to systematically interrogate the mechanisms governing its degradation. These complementary screens unbiasedly identify the HECT ubiquitin ligase HUWE1 as the dominant regulator of ASCL1 stability in small cell lung cancer (SCLC) and resolve a conserved C-terminal phospho-degron centered on Ser207 and terminal Trp/Phe residues that are required for HUWE1 docking and ubiquitin-mediated degradation. Unexpectedly, base editor screening further uncovers a previously unrecognized regulatory module within HUWE1: a short negatively charged helix that functions as an autoinhibitory gate controlling access of phospho-degron substrates to HUWE1. Charge-flipping mutations within this regulatory helix relieve autoinhibition and accelerate degradation of multiple HUWE1 phospho-degron substrates, including ASCL1 and the canonical HUWE1 substrate DDIT4. Stabilization of ASCL1 through degron disruption paradoxically impairs SCLC proliferation, revealing that dynamic proteasome-coupled turnover is required for transcription factor function. Together, these findings reveal molecular rules governing HUWE1 phospho-degron recognition and identify a regulatory gate controlling substrate engagement. They also illustrate a generalizable strategy for resolving degradation mechanisms of undruggable transcription factors in their endogenous cellular context.

ASCL1↗

PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8⁺ effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗