Biomedical subjects

Qin Li

Publications and source records attributed to Qin Li.

4 recordsLinked to original sources

PubMed2026

Natural occurrence of a slow lytic pseudomonas phage in a Pediatric case of multidrug-resistant P. aeruginosa severe pneumonia.

Pseudomonas aeruginosa (P. aeruginosa) is widely distributed in the environment. As an opportunistic pathogen, it commonly causes infections in immunocompromised individuals, including respiratory tract infections and burn wound infections. P. aeruginosa possesses multiple antibiotic resistance mechanisms, including efflux pumps, resistance genes, and population dynamics. Phage therapy is a potential approach for addressing drug-resistant P. aeruginosa infections; however, clinical experience and standardized guidelines for its application in severe pneumonia remain limited. A 14-month-old infant was hospitalized for pneumonia. Four days later, he developed acute pneumonia and was sent to the ICU for 38 days of antibiotic therapy; nonetheless, P. aeruginosa remained detectable in the patient's respiratory secretions. During the clinical course, phage zjk6 was detected from a longitudinal P. aeruginosa isolate in the absence of phage therapy. This finding documents the coexistence of a naturally detected phage and MDR P. aeruginosa during prolonged pneumonia, but does not establish that the phage mediated bacterial clearance or clinical recovery. We performed whole-genome sequencing on P. aeruginosa isolates from patients to ascertain if they were infected by the same infection and assessed their antibiotic resistance using drug sensitivity testing. We isolated phages using the drip technique and double-layer plate method, examined their appearance by transmission electron microscopy, and assessed their biological properties through one-step growth curve analysis and lysis spectrum detection. Genome sequencing and comparative genomic analyses were performed to characterize phage zjk6 and representative bacterial isolates and to evaluate phage-host genomic relatedness. P. aeruginosa was isolated repeatedly during 49 days of treatment. Comparative genomic analysis of representative longitudinal isolates revealed multiple strain backgrounds, including distinct ST508 and ST266 lineages and a closely related ST836 lineage. Phage zjk6 was isolated from the fifth clinical isolate, which served as the propagation/reference host. This phage possesses an elongated tail and a limited lysis spectrum, which is capable of gradually lysing the fifth isolated P. aeruginosa strain. Genomic analysis showed that zjk6 formed plaques and displayed slow lytic behavior under the tested conditions, while also carrying lysogeny-associated regulatory modules, indicating temperate potential rather than a strictly lytic lifestyle. A naturally detected slow lytic Pseudomonas phage may coexist with MDR P. aeruginosa during prolonged infection. These findings support further study of phage-bacterium interactions in clinical infections, while the therapeutic significance of zjk6 requires additional validation.

Antibiotic resistance↗

PubMed2026

Alternative tandem transcription initiation links noncoding variants to human disease through translational control.

Alternative tandem transcription initiation is a pervasive mechanism of gene regulation, yet its genetic impact on human disease remains largely unknown. Here, we systematically quantify the genetic regulation of alternative tandem transcription initiation across 25,859 samples from 49 normal human tissues and 33 tumor tissues. We identify approximately 0.4 million genetic variants associated with alternative transcription initiation in 5295 genes, with 32% operating independently of gene expression. Moreover, we discover 2238 multi-tissue alternative tandem transcription initiation outliers enriched for rare deleterious promoter and 5' UTR variants, demonstrating that both common and rare variants modulate transcription initiation. Strikingly, 74% of disease variants that colocalize with genetic variants regulating alternative transcription initiation cannot be identified through expression quantitative trait loci. Transcriptome-wide association studies identify 614 disease susceptibility genes associated with alternative transcription initiation, including known cancer drivers such as MAFF and MLLT10. Functional validation uncovers OSGEP as a breast cancer risk gene, where the alternative allele lengthens the 5' UTR and reduces protein abundance through upstream open reading frame-mediated translation repression, and suppresses breast cancer cell proliferation. Our findings establish alternative transcription initiation as a major, underappreciated mechanism associating noncoding variation with disease, providing a critical resource for interpreting disease risk loci.

Humans↗

PubMed2026

Identification of highly immunogenic endogenous dsRNAs from cellular MDA5 filaments.

ADAR1 converts adenosine to inosine in endogenous double-stranded RNAs (dsRNAs) to prevent excessive MDA5-driven interferon-stimulated gene expression. The source of endogenous immunogenic dsRNAs remains enigmatic because only a small fraction of ADAR1 substrates activate MDA5, and cellular MDA5 filaments have not been isolated. Here, we couple affinity purification of cellular MDA5 filaments with RNA sequencing to define immunogenic endogenous dsRNAs. Greater than 84% of dsRNAs suppressed by combined DDX3X RNA helicase and ADAR1 base-editing activities were present in MDA5 filaments, compared to less than 1% of dsRNA substrates acted on by ADAR1 alone. Dual substrate dsRNAs consisted of inverted repeats embedded in 3'-UTRs with high base-pair complementarity and longer intervening sequences between repeats, with a minor contribution coming from intermolecular dsRNAs formed by sense and antisense transcripts. Moreover, the majority of dual substrate immunogenic dsRNAs were hyperedited in DDX3X mutant cancers. This reveals the identity of endogenous immunogenic dsRNAs and quality control mechanisms underlying their suppression.

Journal Article↗

PubMed2025

Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation.

The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1LPHD stabilizes the ASH1LBAH fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1LPHD with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L.

Histones↗