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Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and severely limits psychosocial function and quality of life, but no effective medication is currently available. Circular RNAs (circRNAs) have been revealed to participate in the MDD pathological process. Targeted delivery of circRNAs without blood‐brain barrier (BBB) restriction for remission of MDD represents a promising approach for antidepressant therapy. In this study, RVG‐circDYM‐extracellular vesicles (RVG‐circDYM‐EVs) were engineered to target and preferentially transfer circDYM to the brain, and the effect on the pathological process in a chronic unpredictable stress (CUS) mouse model of depression was investigated. The results showed that RVG‐circDYM‐EVs were successfully purified by ultracentrifugation from overexpressed circDYM HEK 293T cells, and the characterization of RVG‐circDYM‐EVs was successfully demonstrated in terms of size, morphology and specific markers. Beyond demonstrating proof‐of‐concept for an RNA drug delivery technology, we observed that systemic administration of RVG‐circDYM‐EVs efficiently delivered circDYM to the brain, and alleviated CUS‐induced depressive‐like behaviours, and we discovered that RVG‐circDYM‐EVs notably inhibited microglial activation, BBB leakiness and peripheral immune cells infiltration, and attenuated astrocyte disfunction induced by CUS. CircDYM can bind mechanistically to the transcription factor TAF1 (TATA‐box binding protein associated factor 1), resulting in the decreased expression of its downstream target genes with consequently suppressed neuroinflammation. Taken together, our findings suggest that extracellular vesicle‐mediated delivery of circDYM is effective for MDD treatment and promising for clinical applications.

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein–associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n. The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.

BRD9 and TAF1(2) have been regarded as significant targets of drug design for clinically treating acute myeloid leukemia, malignancies, and inflammatory diseases. In this study, multiple short molecular dynamics simulations combined with the molecular mechanics generalized Born surface area method were employed to investigate the binding selectivity of three ligands, 67B, 67C, and 69G, to BRD9/TAF1(2) with IC50 values of 230/59 nM, 1400/46 nM, and 160/410 nM, respectively. The computed binding free energies from the MM-GBSA method displayed good correlations with that provided by the experimental data. The results indicate that the enthalpic contributions played a critical factor in the selectivity recognition of inhibitors toward BRD9 and TAF1(2), indicating that 67B and 67C could more favorably bind to TAF1(2) than BRD9, while 69G had better selectivity toward BRD9 over TAF1(2). In addition, the residue-based free energy decomposition approach was adopted to calculate the inhibitor–residue interaction spectrum, and the results determined the gatekeeper (Y106 in BRD9 and Y1589 in TAF1(2)) and lipophilic shelf (G43, F44, and F45 in BRD9 and W1526, P1527, and F1528 in TAF1(2)), which could be identified as hotspots for designing efficient selective inhibitors toward BRD9 and TAF1(2). This work is also expected to provide significant theoretical guidance and insightful molecular mechanisms for the rational designs of efficient selective inhibitors targeting BRD9 and TAF1(2).

TATA-box binding protein-associated factor 1 (TAF1) is the largest component of transcription factor IID, a fundamental multi-protein complex for RNA polymerase II-mediated transcription. TAF1 is essential for promoter recognition, coactivator interaction and normal development. Mutations in TAF1 cause developmental disorders and the lethal neurodegenerative disease X-linked dystonia-Parkinsonism. Our previous work suggested that this approximately 170 kb gene has a more complex set of transcripts than currently catalogued. We therefore undertook a systematic assessment of Taf1 transcription in mouse, given its widespread use as a model organism and its high genetic homology with humans. Using targeted nanopore sequencing, we reveal extensive transcriptional diversity and differential abundance of Taf1 messenger RNAs across brain and body regions. We identified 19 novel transcript variants and multiple novel exons, and we predicted their protein domain architectures and modelled them using AlphaFold. Notably, we observed elevated RNA and protein expression in the cerebellum compared with other brain regions. These findings substantially expand the transcriptional landscape of Taf1 and provide crucial insights to guide the investigation of transcript-specific mechanisms in neurodevelopmental and neurodegenerative disorders, enabling the creation of more accurate disease models.

X-linked dystonia-parkinsonism (XDP), an adult-onset neurodegenerative disorder, is caused by an SVA insertion in the gene, containing a hexanucleotide, the length of which is correlated to the severity of the disease. The SVA insertion moderately disrupts gene expression; however, the underlying disease mechanism remains enigmatic. Here, we characterized a fly model for Taf1 deficiency and performed a pilot RNA sequencing analysis. Subsequently, we validated these findings in Taf1-deficient flies and in XDP patient-derived fibroblasts. We identified an upregulation of genes involved in lipid-dependent energy production as a compensatory mechanism to maintain proper ATP levels. However, studies in XDP patient-derived fibroblasts with minor TAF1 reduction did not confirm these findings. -oxidation is elevated in flies with severe TAF1 reduction but not detected in XDP-patient fibroblasts, suggesting that this compensatory mechanism may only manifest above a critical TAF1 dosage threshold, absent in patient basal conditions. This finding thus suggests that dosage-dependent metabolic responses occur following TAF1 loss.

Class II transactivator (CIITA) is a transcriptional coactivator that regulates γ-interferon-activated transcription of Major Histocompatibility Complex (MHC) class I and II genes. As such, it plays a critical role in immune responses: CIITA deficiency results in aberrant MHC gene expression and consequently in autoimmune diseases such as Type II bare lymphocyte syndrome. Although CIITA does not bind DNA directly, it regulates MHC transcription in two distinct ways - as a transcriptional activator and as a general transcription factor. As an activator, CIITA nucleates an enhanceosome consisting of the DNA binding transcription factors RFX, cyclic AMP response element binding protein, and NF-Y. As a general transcription factor, CIITA functionally replaces the TFIID component, TAF1. Like TAF1, CIITA possesses acetyltransferase (AT) and kinase activities, both of which contribute to proper transcription of MHC class I and II genes. The substrate specificity and regulation of the CIITA AT and kinase activities also parallel those of TAF1. In addition, CIITA is tightly regulated by its various regulatory domains that undergo phosphorylation and influence its targeted localization. Thus, a complex picture of the mechanisms regulating CIITA function is emerging suggesting that CIITA has dual roles in transcriptional regulation which are summarized in this review.

The human fungal pathogen Cryptococcus neoformans poses significant health risks, particularly to immunocompromised individuals, such as those with HIV/AIDS. In this study, we investigate the role of an uncharacterized protein, Taf1, in regulating ATP levels and virulence in C. neoformans . Our previous proteomic analyses confirmed the expression of Taf1, encoded by the gene CNAG_04232. We found that the deletion of the TAF1 gene resulted in the upregulation of 204 genes and the downregulation of 908 genes. Gene Ontology analysis indicated that these regulated genes are associated with metabolic and cellular processes, as well as ATP-dependent activities. Notably, the TAF1 -deficient mutant exhibited impaired growth at elevated temperatures (39°C). Furthermore, in a murine model of infection, mice inoculated with the taf1 Δ mutant demonstrated significantly improved survival compared to those infected with the wild-type strain, suggesting a critical role for Taf1 in virulence. Additionally, KEGG pathway analysis of RNA-Seq and metabolomics data revealed significant alterations in fatty acid biosynthesis and degradation pathways following TAF1 deletion. Collectively, these findings underscore the essential role of Taf1 in modulating cellular energy and its implications for the virulence of C. neoformans , thereby paving the way for potential therapeutic strategies targeting this pathogen.

The transcriptional machinery is essential for gene expression and regulation; dysregulation of transcription can result in a range of pathologies, including neurodegeneration, cancer, developmental disorders and cardiovascular disease. A key component of RNA polymerase II-mediated transcription is the basal transcription factor IID, which is formed of the TATA box-binding protein (TBP) and 14 TBP-associated factors (TAFs), the largest of which is the TAF1 protein, encoded on the X chromosome (Xq13.1). TAF1 is dysregulated in X-linked dystonia–parkinsonism and congenital mutations in the gene are causative for neurodevelopmental phenotypes; TAF1 dysfunction is also associated with cardiac anomalies and cancer. However, how TAF1 contributes to pathology is unclear. Here, we highlight the key aspects of the TAF1 gene and protein function that may link transcriptional regulation with disorders of development, growth and adult-onset disorders of motor impairment. We highlight the need to experimentally investigate the full range of TAF1 messenger RNA variants and protein isoforms in human and mouse to aid our understanding of TAF1 biology. Furthermore, the X-linked nature of TAF1 -related diseases adds complexity to understanding phenotypes. Overall, we shed light on the aspects of TAF1 biology that may contribute to disease and areas that could be addressed for future research and targeted therapeutics.

The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1 ’s molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c.3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

X-Linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease affecting individuals with ancestry to the island of Panay in the Philippines. In recent years there has been considerable progress at elucidating the genetic basis of XDP and candidate disease mechanisms in patient-derived cellular models, but the neural substrates that give rise to XDP in vivo are still poorly understood. Previous studies of limited XDP postmortem brain samples have reported a selective dropout of medium spiny neurons within the striatum, although neuroimaging of XDP patients has detected additional abnormalities in multiple brain regions beyond the basal ganglia. Given the need to fully define the CNS structures that are affected in this disease, we created a brain bank in Panay to serve as a tissue resource for detailed studies of XDP-related neuropathology. Here we describe this platform, from donor recruitment and consent to tissue collection, processing, and storage, that was assembled within a predominantly rural region of the Philippines with limited access to medical and laboratory facilities. Thirty-six brains from XDP individuals have been collected over an initial 4 years period. Tissue quality was assessed based on histologic staining of cortex, RNA integrity scores, detection of neuronal transcripts in situ by fluorescent hybridization chain reaction, and western blotting of neuronal and glial proteins. The results indicate that this pipeline preserves tissue integrity to an extent compatible with a range of morphologic, molecular, and biochemical analyses. Thus the algorithms that we developed for working in rural communities may serve as a guide for establishing similar brain banks for other rare diseases in indigenous populations.