Biology subjects

Marlman, J. M.

Publications and source records attributed to Marlman, J. M..

3 recordsLinked to original sources

bioRxiv2023

Aryl hydrocarbon receptor (AHR) and IL-13 signaling crosstalk in human keratinocytes and atopic dermatitis

Atopic dermatitis (AD) is an allergic skin disease mediated by skin barrier impairment and IL-13-driven immune response. Activation of the aryl hydrocarbon receptor (AHR) has shown promise in early clinical trials for AD, however, the mechanism by which AHR mediates this function is unknown. Herein, AHR signaling is shown to be dysregulated in AD patients using publicly available gene expression data from biopsies of patients with AD compared with controls. AHR target genes, CYP1A1, CYP1A2 and NFE2L2 were decreased in lesional skin compared with healthy control skin (p=0.001, p<1.0*10-10 and p=6.1*10-6 respectively). Single cell RNA sequencing studies demonstrated increased expression of AHR (p<1.0*10-4 and p=0.049) and decreased expression of CYP1A1 in lesional AD keratinocytes compared with healthy control keratinocytes (p=5.0*10-4 and p=0.21). AHR activation reversed IL-13-dependent gene expression of several key genes in AD pathogenesis, most notably the eosinophil chemoattractant, CCL26 (Eotaxin-3). There was substantial overlap between differentially expressed genes in keratinocytes of patients with atopic dermatitis and AHR-regulated genes. Mechanistically, there was evidence for direct transcriptional effects of AHR as its binding motifs were identified in the differentially expressed genes from lesional AD keratinocytes compared to control keratinocytes and AHR activation did not modify IL-13-dependent signal transducer and activator of transcription 6 (STAT6) translocation to the nucleus. Together these data imply that AHR modulates IL-13 downstream signaling in keratinocytes through genome-wide direct transcriptional regulatory effects.

immunology↗

bioRxiv2022

Systematic analysis of transcriptional and epigenetic effects of genetic variation in Kupffer cells enables discrimination of cell intrinsic and environment-dependent mechanisms

Noncoding genetic variation is a major driver of phenotypic diversity but determining the underlying mechanisms and the cell types in which it acts remain challenging problems. Here, we investigate the impact of natural genetic variation provided by phenotypically diverse inbred strains of mice on gene expression and epigenetic landscapes of Kupffer cells. Analysis of gene expression in Kupffer cells and other liver cell types derived from C57BL/6J, BALB/cJ and A/J mice provided evidence for strain-specific differences in environmental factors influencing Kupffer cell phenotypes, including preferential Leptin signaling in BALB/cJ Kupffer cells. Systematic analysis of transcriptomic and epigenetic data from F1 hybrids of these mice, and transcriptomic data from strain-specific Kupffer cells engrafted into a common host enabled quantitative assessment of cis versus trans effects of genetic variation on gene expression and an estimate of cell autonomous versus non cell autonomous effects. Under homeostatic conditions, trans effects of genetic variation were dominant, with the majority of trans regulation being non cell autonomous. In contrast, strain specific responses to acutely administered LPS were primarily associated with genetic variation acting in cis to modify response elements for lineage determining and signal dependent transcription factors. Collectively, these findings reveal cell intrinsic and environmental effects of natural genetic variation on gene expression, demonstrate the use of enhancers as detectors of trans effects of genetic variation, and provide a new resource for understanding the impact of genetic variation on gene expression in Kupffer cells.

genomics↗

bioRxiv2021

Behavioral and postural analyses establish sleep-like states for mosquitoes that can impact interactions with hosts

Sleep is an evolutionarily conserved process that has been described in different animal systems. For insects, sleep characterization has been primarily achieved using behavioral and electrophysiological correlates in a few systems. Sleep in mosquitoes, which are important vectors of disease-causing pathogens, has not been directly examined. This is surprising as circadian rhythms, which have been well studied in mosquitoes, influence sleep in other systems. In this study, we characterized sleep in mosquitoes using body posture analysis and behavioral correlates, and quantified the effect of sleep deprivation on sleep rebound, host landing and blood-feeding propensity. Body and appendage position metrics revealed a clear distinction between the posture of mosquitoes in their putative sleep and awake states for multiple species, which correlate with a reduction in responsiveness to host cues. Sleep assessment informed by these posture analyses indicated significantly more sleep during periods of low activity. Nighttime and daytime sleep deprivation resulting from the delivery of vibration stimuli induced sleep rebound in the subsequent phase in day and night active mosquitoes, respectively. Lastly, sleep deprivation suppressed host landing in both laboratory and field settings and also impaired blood feeding of a human host when mosquitoes would normally be active. These results suggest that quantifiable sleep states occur in mosquitoes, and highlight the potential epidemiological importance of mosquito sleep.

physiology↗