Biology subjects

Glastad, K. M.

Publications and source records attributed to Glastad, K. M..

6 recordsLinked to original sources

bioRxiv2025

Deciphering the role of histone modifications in memory and exhausted CD8 T cells

Exhausted CD8 T cells (TEX) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (TMEM) cells, TEX have a unique open chromatin landscape underlying a distinct gene expression program. How TEX transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (TN), TMEM and TEX. We identified H3K27ac-associated super-enhancers that distinguish TN, TMEM and TEX, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in TN, but activated in TMEM or TEX whereas other genes poised in TN were repressed in TMEM or TEX, indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in TEX, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of TEX compared to TMEM through both activating and repressive pathways.

immunology↗

bioRxiv2025

The fire ant social chromosome exerts a major influence on genome regulation

Supergenes underlying complex trait polymorphisms ensure sets of coadapted alleles remain genetically linked. Despite their prevalence in nature, the mechanisms of supergene effects on genome regulation are poorly understood. In the fire ant Solenopsis invicta, a supergene containing over 500 individual genes influences trait variation in multiple castes to collectively underpin a colony level social polymorphism. Here, we present results of an integrative investigation of supergene effects on gene regulation. We present analyses of ATAC-seq data to investigate variation in chromatin accessibility by supergene genotype and STARR-seq data to characterize enhancer activity by supergene haplotype. Integration with gene coexpression analyses, newly mapped intact TEs, and previously identified CNVs, collectively reveal widespread effects of the supergene on chromatin structure, gene transcription, and regulatory element activity, with a genome-wide bias for open chromatin and increased expression in the presence of the derived supergene haplotype, particularly in regions that harbor intact TEs. Integrated consideration of CNVs and regulatory element divergence suggests each evolved in concert to shape the expression of supergene encoded factors, including several transcription factors that may directly contribute to the trans-regulatory footprint of a heteromorphic social chromosome. Overall, we show how genome structure in the form of a supergene has wide-reaching effects on gene regulation and gene expression.

genomics↗

bioRxiv2024

Neuropeptides specify and reprogram division of labor in the leafcutter ant Atta cephalotes

Social insects offer powerful models to investigate the mechanistic foundation of elaborate individual behaviors comprising a cooperative community. Workers of the leafcutter ant genus Atta provide an extreme example of behavioral segregation among many phenotypically distinct worker types. We utilize the complex worker system of Atta cephalotes to test the molecular underpinnings of behavioral programming and, in particular, the extent of plasticity to reprogramming. We identify specific neuropeptides as mediators of worker division of labor in A. cephalotes, finding two neuropeptides associated with characteristic behaviors of leafcutting and of brood care. Manipulation via genetic knockdown or by injection of these neuropeptides led to stark loss or gain of each behavior and to transcriptomic shifts in the predicted direction, that is, towards gene pathways expressed in the natural caste. We also compare specific A. cephalotes worker transcriptomes with those of orthologous workers of the eusocial mammal, the naked mole rat H. gaber, revealing global similarities between caste-biased expression and link to specific roles of our studied neuropeptides in ants. This work underscores the essential function of neuropeptides in establishing complex social behavior and a remarkable plasticity among individual behavioral types.

molecular biology↗

bioRxiv2022

Hormonal gatekeeping via the blood brain barrier governs behavior

Here we reveal an unanticipated role of the blood-brain-barrier (BBB) in regulating complex social behavior in ants. Using scRNA-seq we find localization in the BBB of a key hormone-degrading enzyme called Juvenile hormone esterase (Jhe), and we show that this localization governs the level of Juvenile Hormone (JH3) entering the brain. Manipulation of the Jhe level reprograms the brain transcriptome between ant castes. While ant Jhe is retained and functions intracellularly within the BBB, we show that Drosophila Jhe is naturally extracellular. Heterologous expression of ant Jhe into the Drosophila BBB alters behavior in fly to mimic what is seen in ant. Most strikingly, manipulation of Jhe levels in ant reprograms complex behavior between worker castes. Our study thus uncovers a novel, potentially conserved role of the BBB serving as a molecular gatekeeper for a neurohormonal pathway that regulates social behavior.

neuroscience↗

bioRxiv2022

Long lifespan is maintained by a unique Heat Shock Factor in reproductive ants

Among eusocial insects, reproductive females show longer lifespan than non-reproductive female workers despite high genetic similarity. Using an ant species (Harpegnathos saltator, Hsal) featuring inducible worker reproduction and correlated extended lifespan, we find that long-lived reproductive individuals (called "gamergates") show elevated expression of heat shock response (HSR) genes specifically in the absence of heat stress. This HSR gene elevation is driven in part by gamergate-specific constitutive upregulation of a heat shock transcription factor gene most similar to mammalian HSF2 (called hsalHSF2). In sterile workers hsalHSF2 is bound to DNA only upon heat stress, but in gamergates hsalHSF2 binds to DNA in the absence of heat stress, and correlates with caste-biased gene expression of a subset of heat-inducible genes, thus showing natural bias to gamergates. Remarkably, ectopic expression in D. melanogaster of hsalHSF2 leads to enhanced survival compared to hsalHSF1 following heat stress, as well as extended lifespan. Molecular characterization of these longer-lived flies illustrates multiple parallels between long-lived flies and gamergates, underscoring the centrality of hsalHSF2 to extended lifespan in gamergates. Hence, ant caste-specific heat stress resilience and excessive longevity is, remarkably, transferrable to flies via a specialized ant heat shock factor, HSF2. These findings reinforce the critical role of proteostasis to health and to aging, and reveal novel mechanisms underlying facultative lifespan extension.

genomics↗

bioRxiv2019

Social reprogramming in ants induces longevity-associated glia remodeling

Healthy brain aging is of crucial societal importance; however, the mechanisms that regulate it are largely unknown. Social insects are an outstanding model to study the impact of environment and epigenetics on brain function and aging because workers and queens arise from the same genome but display profound differences in behavior and longevity. In Harpegnathos saltator ants, adult workers can transition to a queen-like phenotypic state called gamergate. This caste transition results in reprogramming of social behavior and lifespan extension. Whether these changes in brain function and physiology cause brain remodeling at the cellular level is not known. Using single-cell RNA-sequencing of Harpegnathos brains undergoing caste transition, we uncovered shifts in neuronal and glial populations. In particular, the conversion of workers into long-lived gamergates caused the expansion of ensheathing glia, which maintain brain health by phagocytosing damaged neuronal structures. These glia cells were lost during aging in normal workers but not in longer-lived gamergates. We observed similar caste- and age-associated differences in ensheathing glia in other Hymenoptera as well as Drosophila melanogaster. We propose that enhanced glia-based neuroprotection promotes healthy brain aging and contributes to the extended lifespan of the reproductive caste in social insects.

neuroscience↗