Biology subjects

Wright, C. M.

Publications and source records attributed to Wright, C. M..

6 recordsLinked to original sources

bioRxiv2026

Centromeric α-satellite DNA is a hotspot of genotoxic damage, incomplete repair, and cytoplasmic mislocalization

Centromeric -satellite DNA constitutes a highly repetitive and structurally specialized component of the human genome, yet the mechanisms underlying its damage susceptibility and repair fidelity under genotoxic stress remain undefined. Here, we demonstrate that genotoxic stress preferentially targets active centromeres, generating DNA double-strand breaks (DSBs) within -satellite arrays. Using bleomycin as a defined genotoxic perturbation, we identify dynamic alterations in centromeric repeat content, manifesting as net copy number losses and gains across multiple chromosome-specific -satellite arrays following damage. Similar centromere-associated damage signatures are observed in fibroblasts from patients with limited cutaneous systemic sclerosis, indicating that these features extend beyond experimental systems. Centromeric DSBs engage ATM-dependent DNA damage signaling and are repaired predominantly through RAD51-associated homologous recombination; however, repair fails to fully restore centromeric integrity. This incomplete repair is associated with defects in kinetochore organization, chromosome missegregation, and the formation of micronuclei containing centromeric DNA. Notably, [~]30% of these structures retain CENP-B but lacks detectable CENP-A, indicating disruption of centromere chromatin organization. Centromeric chromatin is frequently mislocalized to the cytoplasm following nuclear envelope perturbation, where immunofluorescence analysis reveals proximity to MHC class II (HLA-DRB1). Together, these findings establish centromeric -satellite DNA as a vulnerability hotspot under genotoxic stress, with implications for chromosome instability and chromatin antigen exposure in fibrosis-associated autoimmunity.

genetics↗

bioRxiv2024

Chromatin regulator HELLS mediates SSB repair and responses to DNA alkylation damage.

The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair, and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/629292v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@2bbd3eorg.highwire.dtl.DTLVardef@1956f14org.highwire.dtl.DTLVardef@1afcb7corg.highwire.dtl.DTLVardef@58504c_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Bowel dysmotility and enteric neuron degeneration in lysosomal storage disease mice is prevented by gene therapy

Background and aimsChildren with neurodegenerative disease often have debilitating gastrointestinal (GI) symptoms that may be due at least in part to underappreciated involvement of neurons in the enteric nervous system (ENS), the master regulator of bowel function. MethodsWe investigated bowel motility in mouse models of CLN1 and CLN2 disease, neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 (PPT1) and tripeptidyl peptidase-1 (TPP1), respectively. We then explored the integrity of ENS anatomy in immunostained bowel wholemount preparations from these mice. Lastly, we administered adeno-associated viral gene therapy to neonatal mice and determined if this would prevent these newly identified bowel phenotypes. ResultsMouse models of CLN1 and CLN2 disease both displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Neonatal administration of adeno-associated virus-mediated gene therapy prevented bowel transit defects and the loss of many ENS neurons. ConclusionsWe show that two neurodegenerative lysosomal storage diseases cause profound and progressive damage to the mouse enteric nervous system and impair bowel motility. We also provide proof-of-principle evidence that gene therapy can prevent enteric nervous system disease. This study may have general therapeutic implications for many inherited neurodegenerative disorders. What you need to knowO_ST_ABSBackground and ContextC_ST_ABSMany pediatric central nervous system disorders also have debilitating gastrointestinal symptoms. For most of these diseases, it is not known if the enteric nervous system (ENS) is also affected and to what degree ENS defects contribute to GI symptoms. To date, no attempts have been made to directly treat or prevent enteric nervous system disease via gene therapy. New FindingsThe enteric nervous system is severely affected in mouse models of CLN1 and CLN2 disease, profoundly neurodegenerative lysosomal storage disorders. Bowel transit defects and most of the enteric nervous system pathology can be prevented by neonatal administration of gene therapy. LimitationsInformation about enteric nervous system disease in human children is still lacking, and methods will need to be developed to treat the human bowel. ImpactThese findings identify an underappreciated effect of neurodegenerative disease upon the bowel and demonstrate that enteric nervous system degeneration can be prevented in mice. This provides a new perspective on these childhood disorders that may be applicable to many other conditions that affect the bowel. Lay SummaryIn childrens diseases where the brain degenerates, nerve cells in the bowel also die causing gastrointestinal problems, but this can be prevented by gene therapy.

neuroscience↗

bioRxiv2022

Single Nucleus Sequencing of Human Colon Visceral Smooth Muscle Cells, PDGFRα Cells, and Interstitial Cells of Cajal

Background and AimsSmooth muscle cells (SMCs), Interstitial cells of Cajal (ICCs), and PDGFR+ cells (PCs) form a functional syncytium in the bowel known as the SIP syncytium. The SIP syncytium works in concert with the enteric nervous system (ENS) to coordinate bowel motility. However, our understanding of individual cell types that form this syncytium and how they interact with each other remains limited, with no prior single cell RNAseq analyses focused on human SIP syncytium cells. MethodsWe analyzed single-nucleus RNA sequencing data from 10,749 human colon SIP syncytium cells (5572 SMC, 372 ICC, and 4805 PC nuclei) derived from 15 individuals. ResultsConsistent with critical contractile and pacemaker functions and with known ENS interactions, SIP syncytium cell types express many ion channels including mechanosensitive channels in ICCs and PCs. PCs also prominently express ECM-associated genes and the inhibitory neurotransmitter receptor for vasoactive intestinal peptide (VIPR2), a novel finding. We identified two PC clusters that differ in expression of many ion channels and transcriptional regulators. Interestingly, SIP syncytium cells co-express 6 transcription factors (FOS, MEIS1, MEIS2, PBX1, SCMH1, and ZBTB16) that may be part of a combinatorial signature that specifies these cells. Bowel region-specific differences in SIP syncytium gene expression may correlate with regional differences in function, with right (ascending) colon SMCs and PCs expressing more transcriptional regulators and ion channels than SMCs and PCs in left (sigmoid) colon. ConclusionThese studies provide new insights into SIP syncytium biology that may be valuable for understanding bowel motility disorders and lead to future investigation of highlighted genes and pathways. SynopsisIn this first single nucleus RNASeq analysis of human SIP syncytium, we identify novel features of SIP syncytium cells, including two types of PDGFR+ cells, a SIP-specific combinatorial transcription factor signature, and colon region differences in gene expression.

cell biology↗

bioRxiv2019

DIVISION OF LABOR INCREASES WITH COLONY SIZE, REGARDLESS OF GROUP COMPOSITION, IN THE SOCIAL SPIDER STEGODYPHUS DUMICOLA

AO_SCPLOWBSTRACTC_SCPLOWDivision of labor (DOL) is a pattern of work organization where individual group members specialize on different tasks. DOL is argued to have been instrumental for the success of eusocial insects, where it scales positively with group size both within and across species. Here we evaluate whether DOL scales positively with group size in a society of cooperative breeders (social spiders) and whether this pattern is impacted by the behavioral composition of the group. To do this we engineered experimental colonies of contrasting group sizes and behavioral compositions and tracked individuals participation in two colony maintenance tasks: prey capture and web construction. As with some eusocial insects, we found that larger groups exhibited DOL metrics up to 10-times greater than smaller groups, conveying that individuals specialize on particular tasks more in larger colonies. This scalar relationship did not differ by a groups behavioral composition, though groups composed of only bold spiders exhibited reduced DOL relative to all-shy or mixed groups. We also found that per capita participation in prey capture, but not web construction, decreased as a function of group size. This suggests that individuals in larger groups may save energy by reducing their involvement in some tasks. Together, our results convey that similar scalar relationships between DOL and group size can emerge both inside and outside the eusocial insects. Thus, theory developed for understanding DOL in eusocial societies may inform our understanding of group function in a larger swath of animal social diversity than is broadly appreciated.\n\nSO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWDivision of labor (DOL) has been a major area of research in the eusocial insects for decades, and is argues to underlie their ecological success. Only recently have other social arthropods, such as social spiders, been considered for studies concerning DOL. Given their smaller colony sizes, and absence of morphological castes, DOL was not thought to be an important facet of spider societies. However, we found that spider societies do indeed exhibit high degrees of DOL that is positively correlated to colony size, as seen in many eusocial insects. These findings suggest that the scalar relationship between group size and social organization seen in social insects is likely generalizable to a larger diversity of social taxa, and that cooperative breeders can show levels of division of labor equaling or exceeding those of eusocial systems evaluated to date.

animal behavior and cognition↗

bioRxiv2019

Foundress Number, But Not Queen Size Or Boldness, Predicts Colony Life-History In Wild Paper Wasps

Colonies of social insects exhibit a spectacular variety of life histories. Here we documented the degree of variation in colony life-history traits, mostly related to productivity, in two species of wild paper wasps. We then tested for associations between colony life-history traits to look for trade-offs or positively associated syndromes, and examined whether individual differences in the behavioral tendencies of foundresses (Polistes metricus) or the number of cofoundresses (P. fuscatus) influenced colony life-history. The majority of our measures of colony life-history were positively related, indicating no obvious resource allocation trade-offs. Instead, the positive association of traits into a productivity syndrome appears to be driven by differences in queen or microhabitat quality. Syndrome structure differed only marginally between species. Queen boldness and body size were not associated with colony life-history in P. metricus. Colonies initiated by multiple P. fuscatus foundresses were generally more productive, and this advantage was approximately proportional to the number of cofoundresses. These findings demonstrate that colony life-history traits can be associated together much like individual life-history traits, and the associations seen here convey that differences in overall productivity drive between-colony differences in life-history.

ecology↗