Biology subjects

Small, E. M.

Publications and source records attributed to Small, E. M..

5 recordsLinked to original sources

bioRxiv2025

Deletion of RSK2 kinase alleviates age-dependent hypertension

BackgroundHypertension prevalence increases with age, reaching over 70% of people over age 65. The underlying mechanisms are poorly understood. This study interrogates a new signaling pathway in vascular smooth muscle of aged mice driven by p90 ribosomal S6 kinase, RSK2, and its role in increasing peripheral vascular resistance and blood pressure (BP). MethodsBasal BP measurements were taken at 26-29 month (812-892 day) old mice with global deletion of RSK2 (Rsk2-/-) prior to and following treatment with L-NAME. Cardiac function, vessel stiffness, myogenic responses, Ca2+events, contractility, immuno-staining, histology studies and western blotting were performed. ResultsResting BP and myogenic vasoconstriction were normal in aged global Rsk2-/- mice and elevated in wild type (WT) littermates. L-NAME treatment increased BP in aged Rsk2+/+ but not aged Rsk2-/-. Vessel stiffness and glycation collagen crosslinking increased in both aged Rsk2+/+ and Rsk2-/- compared to young vessels with no remodeling or increase in collagen content, even though BP in aged Rsk2-/- arterioles was normal. Increased vessel stiffness was dissociated from increased BP. Ca2+ transients increased and sensitivity to NO-induced relaxation decreased in aged Rsk2+/+ compared to young WT arterioles. IEL structures, eNOS and Hb distribution at myoendothelial junctions were disturbed impairing vasorelaxation in aged Rsk2+/+ but not aged Rsk2-/- arterioles. ConclusionsRSK2 plays a significant role in hypertension associated with aging by downregulating prorelaxant signaling and promoting procontractile events in the vasculature, offering potential new therapeutic targets.

physiology↗

bioRxiv2024

PERCEPTIVE: an R Shiny pipeline for the prediction of epigenetic modulators in novel species

Epigenetic processes play key roles in regulating gene expression, genome stability, and metabolic output in organisms across the tree of life. Yet, the role epigenetics plays in regulating genomes and behaviors remains underdeveloped for microalgae, particularly as new species are identified and characterized. This is likely due to the cumbersome nature and species-dependent attributes of epigenetic wet-lab methodologies, which preclude the rapid identification of epigenetic modifications and modulators. However, there is extraordinary conservation of epigenetic processes from budding yeast to humans; in many cases, one may infer how behavior and function are epigenetically regulated in novel species by simply identifying epigenetic modulators, or the proteins responsible for conferring epigenetic modifications. To this end, we have developed a graphical software package, titled PERCEPTIVE (pipeline for the prediction of epigenetic modulators in novel species). This novel platform solely uses the genomic sequence of an organism, and preexisting information from model species, to predict the epigenetic modulators and associated modifications in a novel species. Predictions are presented to the user in a graphical interface, which provides literature-based interpretation of results, enabling users to quickly understand potential epigenetic processes in their species of interest and plan follow-up experiments. To test PERCEPTIVE, we predicted epigenetic modulators in several feedstock candidate algae species. To validate these predictions, wet-lab studies were performed, including mass spectrometry; these results underscore the high accuracy of PERCEPTIVE predictions. Overall, PERCEPTIVE represents a powerful tool for the research and manipulation of algal species, which does not require a priori knowledge of epigenetics and is accessible to a broad set of investigators.

genomics↗

bioRxiv2024

FZD2 inhibits YAP and prevents cell cycle reentry in adult murine cardiomyocytes

RationaleFully differentiated cardiomyocytes (CMs) are post-mitotic and cannot repopulate damaged tissue after myocardial infarction (MI). Understanding the mechanisms preventing CM proliferation or promoting their survival after injury may lead to treatment strategies for MI. While the effects of canonical WNT/{beta}-catenin signaling in adult CMs have been examined, roles for non-canonical WNT signaling in cardiac homeostasis and repair remain unexplored. ObjectiveTo determine the function of the non-canonical WNT receptor frizzled 2 (FZD2) in adult cardiac homeostasis and injury. Methods and ResultsFZD2 was deleted from the CMs of adult mice to investigate its role in myocardial homeostasis. Fzd2 conditional knockout (CKO) mice had cardiomegaly but not hypertrophy. FZD2-deficient CMs expressed proliferation and cytokinesis markers, suggesting that they have increased proliferation potential. FZD2-deletion caused the accumulation of {beta}-catenin. However, {beta}-catenin localized to the membranes of FZD2-deficient CMs and did not activate target gene expression. Instead, the YES-associated protein (YAP) regulated genes v-myc avian myelocytomatosis viral oncogene 1 (Mycl), and B cell leukemia/lymphoma 2 (Bcl2l1) were upregulated in Fzd2 CKO CMs relative to controls. Knockdown of FZD2 increased YAP activity in neonatal ventricular CMs (NVCMs), while overexpressing FZD2 inhibited YAP. Neither {beta}-catenin knockdown nor mutating the large tumor suppressor 1 and 2 (LATS1/2) target site on YAP blocked the effects of FZD2 on YAP in NVCMs, suggesting that FZD2 utilizes different effectors than canonical WNT and Hippo signaling. Fzd2 CKO and control mice were subjected to MI to determine if FZD2-deletion affects cardiac repair. While ischemia and necrosis were similar 24 hours post MI, Fzd2 CKO mice had better cardiac function and less scarring than controls. ConclusionsFZD2 reduces YAP activity and prevents adult murine CMs from reentering the cell cycle. FZD2-deletion improves heart function and reduces scarring in mice after MI, implicating FZD2 as a target for pharmacological intervention.

cell biology↗

bioRxiv2024

Epigenomic manipulation reveals the relationship between locus specific chromatin dynamics and gene expression

Dysregulation of epigenetic processes leads to a plethora of abnormalities including disease states such as cancer. Therapies focused on epigenetic modulation alter gene expression to correct dysfunction, though the mechanisms and perpetuation of these states is unknown. Here, we use integrated epigenomics and three-dimensional chromatin structure-function analyses after acute histone deacetylase inhibitor cancer drug treatment (suberoylanilide hydroxamic acid in lung cancer cells). Treatment induced substantial (13%) genomic rearrangement that rebounds despite persistent gene expression changes and spreading of acetylation. The chromatin functional landscape (accessibility, active transcription modification, and gene expression) is controlled and locus-specific, while chromatin contacts are globally altered resulting in a moderate weakening of topologically associating domains. Chromatin states are more dynamic at transcriptionally active loci while genes with reduced expression are epigenetically stable suggesting chromatin architectural turnover and nucleosome remodeling is locus-specific and underlies the bidirectional expression changes. Thus, local 3D chromatin and genome structural dynamics is integral for loci regulation in response to epigenomic perturbation. The partial persistence of these altered features may have larger implications for efficacy of epigenetic drugs in amelioration of disease states.

cancer biology↗

bioRxiv2023

Vaccinia virus infection induces concurrent alterations in host chromatin architecture, accessibility, and gene expression

Genomic DNA folds into complex configurations that produce particular local and global structures thought to profoundly impact genome function. To understand the dynamic nature of this relationship, we investigated the extent of host chromatin structural and functional changes in response to a viral agent. We performed comprehensive assessments of host architecture (Hi-C), accessibility (ATAC-seq), and gene expression (RNA-seq) in a paired manner in response to attenuated vaccinia (smallpox) virus. Over time, infection significantly increased long-range intra-chromosomal interactions and decreased chromatin accessibility. Fine-scale accessibility changes were independent of broad-scale chromatin compartment exchange, which increased (up to 12% of the genome) over time, underscoring potential independent mechanisms for global and local chromatin reorganization. The majority of differentially expressed genes, including those downregulated in immune responses, had concurrent alterations in local accessibility and loop domain restructuring. Increased B compartmentalization, intra-chromosomal interactions, and decreased inter-chromosomal interactions and chromatin accessibility together indicate that infection converts the host genome into a more condensed state with nearly equal bidirectional differential gene expression. These changes in host chromatin features may have implications for developing efficacious anti-viral countermeasures. Overall, our empirical data provides evidence of orchestrated concurrent alterations in chromatin architecture, accessibility, and gene expression in response to infection, further reinforcing the notion of coordinated structure-function dynamics of the genome.

genomics↗