Biology subjects

Jaiswal, J.

Publications and source records attributed to Jaiswal, J..

5 recordsLinked to original sources

bioRxiv2024

Dysregulated airway epithelial antiviral immunity in Down Syndrome impairs type III IFN response and amplifies airway inflammation during RSV infection.

Trisomy 21 (TS21), also known as Down syndrome (DS), increases pediatric mortality risk from respiratory syncytial virus (RSV) by nine-fold, yet its underlying immunological basis remains unclear. Here, we investigated RSV-induced immunological responses in TS21 airway epithelial cells (AECs), the primary site of respiratory virus entry and host defense. TS21 AECs exhibit hyperactive interferon (IFN) signaling and reduced RSV infectivity, but they also show impaired type-III IFN responses during viral infection. Furthermore, TS21 AECs demonstrate heightened production of proinflammatory mediators CXCL5 and CXCL10 both before and after RSV exposure. Infants with DS suffering from severe viral bronchiolitis demonstrate dysregulated airway immune responses in vivo, characterized by diminished type-III IFN levels and increased CXCL5/CXCL10 secretion. Our results indicate that RSV severity in DS is not due to impaired viral control but to dysregulated airway proinflammatory responses, offering new therapeutic opportunities to mitigate the severity of RSV infection in children with DS.

immunology↗

bioRxiv2023

Telomeres control regulation of the human Telomerase (hTERT) gene through non-telomeric TRF2 and independent of Telomere looping

The function of the human telomerase reverse transcriptase (hTERT) in the synthesis and maintenance of chromosome ends, or telomeres, is widely understood. Whether and how telomeres, on the other hand, influence hTERT regulation is relatively less studied. We found hTERT was transcriptionally altered depending on telomere length (TL). This resulted from TL-dependent binding of TRF2 between telomeres and the hTERT promoter. hTERT promoter-bound TRF2 was non-telomeric and did not involve the looping of telomeres to the hTERT promoter. Cell lines from different tissue types (fibrosarcoma (HT1080), colon cancer (HCT116), and breast cancer (MDA-MB-231), engineered for either telomere elongation/shortening gave increase/decrease in hTERT, respectively. Mechanistically, we show hTERT promoter-bound non-telomeric TRF2 recruits the canonical PRC2-complex inducing repressor histone H3K27-trimethylation in a TL-dependent fashion. This was further supported by TL-dependent promoter activity from an exogenously inserted hTERT reporter. Increase in TL over days followed by gradual decline, resulted in activation followed by repression of hTERT in a concerted manner, further implicating TL as a key factor for hTERT regulation. Notably on reprogramming primary fibroblasts to induced pluripotent stem cells (iPSCs), TRF2 loss from the hTERT promoter was evident along with telomere elongation and hTERT upregulation. Conversely, on telomere shortening in iPSCs, hTERT promoter-bound TRF2 was restored with marked reduction in hTERT further supporting the causal role of TL in hTERT transcription. Mechanisms of tight control of hTERT by TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing and pluripotency. TeaserTelomere length controls hTERT expression by modulating TRF2 distribution and PRC2-mediated repression, highlighting a self-regulatory mechanism in cancer.

cancer biology↗

bioRxiv2023

Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis

The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3+ macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3+ phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3+ macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.

immunology↗

bioRxiv2022

Mutual repression between JNK/AP-1 and JAK/STAT stratifies cell behaviors during tissue regeneration

Epithelial repair relies on the activation of stress signaling pathways to coordinate cellular repair behaviors. Their deregulation is implicated in chronic wound and cancer pathologies. Despite such translational importance, an understanding of how spatial patterns of signaling pathways and repair behaviors arise in damaged tissues remains elusive. Using TNF-/Eiger-mediated inflammatory damage to Drosophila imaginal discs, we uncover that JNK/AP-1 signaling cells act as paracrine organizers and initiate a mutual repression network that spatially segregates JNK/AP-1 and JAK/STAT signaling cells into distinct populations. While JNK/AP-1 signaling cells produce JAK/STAT-activating Upd ligands, these signal-sending cells suppress activation of JAK/STAT via Ptp61F. Conversely, responding cells with activated JAK/STAT suppress JNK activation via Zfh2. The resulting bistable segregation of signaling domains is associated with distinct cellular tasks and regenerative potential. While JNK/AP-1 signaling cells at the wound center act as paracrine organizers, their cell cycle is senescently arrested. Thus, compensatory proliferation occurs exclusively in JAK/STAT signaling cells at the wound periphery. This spatial stratification is essential for proper tissue repair, as co-activation of JNK/AP-1 and JAK/STAT in the same cells creates conflicting inputs on cell cycle progression, leading to excess apoptosis of senescently arrested organizer cells. Finally, we demonstrate that bistable spatial segregation of JNK/AP-1 and JAK/STAT drives senescent and proliferative behaviors in transient as well as chronic tissue damage models, and importantly, in RasV12, scrib tumors under the influence of JNK/AP-1 activity. Revealing this previously uncharacterized regulatory network between JNK/AP-1, JAK/STAT and associated cell behaviors have important implications for our conceptual understanding of tissue repair, chronic wound pathologies and tumor microenvironments, where both pathways are strongly implicated.

developmental biology↗

bioRxiv2020

A new long-read RNA-seq analysis approach identifies and quantifies novel transcripts of very large genes

RNA-seq is widely used for studying gene expression, but commonly used sequencing platforms produce short reads that only span up to two exon-junctions per read. This makes it difficult to accurately determine the composition and phasing of exons within transcripts. Although long-read sequencing improves this issue, it is not amenable to precise quantitation, which limits its utility for differential expression studies. We used long-read isoform sequencing combined with a novel analysis approach to compare alternative splicing of large, repetitive structural genes in muscles. Analysis of muscle structural genes that produce medium (Nrap -5kb), large (nebulin - 22 kb) and very-large (titin - 106 kb) transcripts in cardiac muscle, and fast and slow skeletal muscles identified unannotated exons for each of these ubiquitous muscle genes. This also identified differential exon usage and phasing for these genes between the different muscle types. By mapping the in-phase transcript structures to known annotations, we also identified and quantified previously unannotated transcripts. Results were confirmed by endpoint PCR and Sanger sequencing, which revealed muscle-type specific differential expression of these novel transcripts. The improved transcript identification and quantification demonstrated by our approach removes previous impediments to studies aimed at quantitative differential expression of ultra-long transcripts.

genomics↗