MicroRNAs (miRNAs) are trans-acting small regulatory RNAs that work coordinately with transcription factors (TFs) to shape the repertoire of cellular mRNAs available for translation. Despite our growing knowledge of individual plant miRNAs, their global roles in gene regulatory networks remain mostly unassessed. Based on interactions obtained from public databases and curated from the literature, we reconstructed an integrated miRNA network in Arabidopsis that includes 66 core TFs, 318 miRNAs, and 1712 downstream genes. We found that miRNAs occupy distinct niches and enrich miRNA-containing feed-forward loops (FFLs), particularly those with miRNAs as intermediate nodes. Further analyses revealed that miRNA-containing FFLs coordinate TFs located in different hierarchical layers and that intertwined miRNA-containing FFLs are associated with party and date miRNA hubs. Using the date hub MIR858A as an example, we performed detailed molecular and genetic analyses of three interconnected miRNA-containing FFLs. These analyses revealed individual functions of the selected miRNA-containing FFLs and elucidated how the date hub miRNA fulfills multiple regulatory roles. Collectively, our findings highlight the prevalence and importance of miRNA-containing FFLs, and provide new insights into the design principles and control logics of miRNA regulatory networks governing gene expression programs in plants.

Mouse somatic cells can be chemically reprogrammed into pluripotent stem cells (CiPSCs) through an intermediate extraembryonic endoderm (XEN)-like state. However, it is elusive how the chemicals orchestrate the cell fate alteration. In this study, we analyze molecular dynamics in chemical reprogramming from fibroblasts to a XEN-like state. We find that Sox17 is initially activated by the chemical cocktails, and XEN cell fate specialization is subsequently mediated by Sox17 activated expression of other XEN master genes, such as Sall4 and Gata4. Furthermore, this stepwise process is differentially regulated. The core reprogramming chemicals CHIR99021, 616452 and Forskolin are all necessary for Sox17 activation, while differently required for Gata4 and Sall4 expression. The addition of chemical boosters in different phases further improves the generation efficiency of XEN-like cells. Taken together, our work demonstrates that chemical reprogramming is regulated in 3 distinct “prime–specify–transit” phases initiated with endogenous Sox17 activation, providing a new framework to understand cell fate determination.

Epilepsy is a heritable neurological disorder that is frequently comorbid with sleeping difficulties, including short/long sleep duration and insomnia. Although epidemiological studies have consistently reported the comorbidity between sleep disturbances and epilepsy, the shared genetic architecture and molecular mechanisms underlying this relationship remain poorly characterized, hindering therapeutic development. In this study, we integrated large-scale genome-wide association study (GWAS) summary statistics of European ancestry to dissect the genetic and molecular links between sleep traits and epilepsy. Using LDSC and GWAS-pw, we identified modest but statistically significant (Bonferroni-corrected) global and local genetic correlations between sleep behaviors and epilepsy. Subsequent CPASSOC cross-trait meta-analysis and transcriptome-wide association studies (TWAS) pinpointed specific pleiotropic loci and shared candidate genes, including SPAG7, VRK2, and LINC00925, which are functionally associated with neuroimmune signaling. While preliminary Phenome-Wide Association Study (PheWAS) profiling of these candidate targets did not identify major adverse associations in current databases, we emphasize that rigorous in vitro and in vivo experimental validations are required before considering them for therapeutic strategies. Finally, pleiotropy-robust bidirectional Mendelian Randomization (MR) analyses suggested unidirectional causal liability from epilepsy to short sleep duration. Although the estimated causal effect size was minimal, it reflects lifelong polygenic architecture rather than acute clinical magnitude. In conclusion, our multi-omics approach unveils the shared genetic architecture of the sleep-epilepsy axis and highlights potential biomarkers for future functional investigation.

BioStudies – one package for all the data supporting a study

Chemical reprogramming holds transformative potential for regenerative medicine. However, the regulatory mechanisms governing cell fate transitions are not well understood. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a barrier to multi-lineage reprogramming. Pharmacological inhibition of IRAK4 enhances the reprogramming of mouse embryonic fibroblasts (MEFs) through a chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, increasing colony formation, and the expression of core XEN regulators (Sox17, Gata4, Sall4, and Foxa2). Genetic knockdown of Irak4 similarly accelerates reprogramming, whereas its overexpression blocks cell fate transitions. IRAK4 inhibition enhances chromatin accessibility and reshapes cell cycle dynamics, characterized by G0/G1 shortening and G2/M lengthening, potentially contributing to multi-lineage state establishment. Furthermore, IRAK4 suppression enhances the direct conversion of MEFs to neuron-like and hepatocyte-like cells, which exhibit enhanced functional maturity, including increased glycogen storage and improved detoxification capacity. Our findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics.

Aim: Alzheimer’s disease (AD) and migraine are both common and heritable neurological disorders. Epidemiological studies repeatedly report an association between migraine and an increased risk of AD. However, whether this co-occurrence reflects shared molecular etiology remains unclear. Methods: We integrated large-scale genome-wide association study (GWAS) summary statistics, AD (Ncase = 21,982 and Ncontrol = 41,944), overall migraine (Ncase = 26,894 and Ncontrol = 374,605), migraine with aura (MA, Ncase = 11,757 and Ncontrol = 374,605), and migraine without aura (MO, Ncase = 9,690 and Ncontrol = 374,605), to perform genome-wide cross-trait meta-analysis (CPASSOC), functional annotation and transcriptome-wide association studies (TWAS) to elucidate the genetic etiology between AD and migraine in detail. Results: Genome-wide cross-trait analysis revealed that 11 independent suggestive shared loci (PCPASSOC < 5 × 10-8 and Psingle-trait < 0.05) and 3 significant shared loci (PCPASSOC < 5 × 10-8 and Psingle-trait < 5 × 10-3) for AD and migraine, with substantial subtype specificity. In addition, after global false discovery rate (FDR) correction across 49 tissues, we identified C2 as a highly significant shared pleiotropic gene in the brain cerebellar hemisphere, and TSBP1-AS1 in the thyroid for AD and MA. Finally, drug-target prioritization highlighted C2 as a candidate therapeutic target, while PheWAS analysis revealed no significant associations between C2 and major disease categories, supporting its limited phenotypic pleiotropy. Conclusion: This study clarified the pleiotropic loci and shared genes underlying AD and migraine by integrating multi-omics. These findings provide important insights into the molecular mechanisms between AD and migraine, and potential candidate genes for further functional validation.