Biology subjects

Mickler, E. A.

Publications and source records attributed to Mickler, E. A..

3 recordsLinked to original sources

bioRxiv2025

Cigarette Smoke and Decreased DNA Repair by Xeroderma Pigmentosum Group C Use a Double Hit Mechanism for Epithelial Cell Lung Carcinogenesis

Emerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely understood role in lung tumorigenesis and concurrent lung diseases, such as chronic obstructive lung disease (COPD). In this study, we investigated the interplay between cigarette smoke, DNA damage and repair, focusing on the Nucleotide Excision Repair (NER) protein Xeroderma Pigmentosum Group C (XPC). We found decreased XPC mRNA expression in most NSCLCs compared to subject-matched, non-cancerous lung. In non-cancerous bronchial epithelial cells, cigarette smoke decreased NER, increased total DNA damage and resultant apoptosis, each exacerbated by XPC deficiency. In contrast, lung cancer cells exhibit greater resilience to cigarette smoke, requiring higher doses to induce comparable DNA damage and apoptosis, and are less reliant on XPC expression for survival. Importantly, XPC protects against chromosomal instability in benign bronchial epithelial cells, but not in lung cancer cells. Our findings support a "double hit" mechanism wherein early decreased XPC expression and resultant aberrant DNA repair, when combined with cigarette smoke exposure, may lead to loss of non-malignant epithelial cells (as observed in COPD), and contributes to early NSCLC transition through altered DNA damage response.

cancer biology↗

bioRxiv2024

Loss of Tbx4 Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the precapillary pulmonary arteries. Genomic variation within the T-box 4 (TBX4) transcription factor is the second most common genetic cause of PAH, and can also cause severe lung developmental disorders with neonatal PH. Currently, the effect of TBX4 loss-of-function on later stages of lung development and predisposition to lung disease, including PH, is not well understood. Therefore, we have generated Tbx4 conditional knockout (Tbx4-CKO) mice in which Cre recombinase deletes exon 5 of Tbx4 within the embryonic lung mesenchyme to create a null allele. We harvested lungs from these mice at various timepoints to examine alveologenesis, vascularization, vascular remodeling, lung cellular composition, and disruption of transcriptional activity compared with control lungs. Right ventricular systolic pressure (RVSP) was measured in six-month-old mice to evaluate for PH. Tbx4-CKO lungs show enlargement of airspaces, as confirmed by an increase in mean linear intercept at P14 (24.9%), P36 (31.5%), and P180 (49.6%). These lungs also show a 39.3% decrease in von Willebrand Factor-positive vessels and a 14.2% increase in vessel wall thickness. Consistent with these results, Tbx4-CKO mice show a statistically significant increase of 15.7% in RVSP and 16.3% in the Fulton index. Bulk-RNA sequencing analysis revealed enrichment of pathways and genes relevant to lung alveologenesis, angiogenesis, and PH. Our results show that disruption of Tbx4 expression during early lung development is sufficient to disrupt postnatal lung development and circulation.

genetics↗

bioRxiv2023

Integrative Multiomics to Dissect the Lung Transcriptional Landscape of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.

genomics↗