Biology subjects

Hwa, J.

Publications and source records attributed to Hwa, J..

3 recordsLinked to original sources

bioRxiv2025

Canonical nuclear envelope protein emerin regulates structure and integrity of the erythrocyte plasma membrane

Red blood cells (RBC) are essential for the survival of aerobic organisms. Mutations in RBC plasma membrane proteins can give rise to a spectrum of diseases characterized by hemolysis, inefficient gas exchange, and anemia. We tested whether emerin (EMD), a nuclear envelope (NE) protein, is also expressed in anuclear cell types to regulate membrane structure and function. We find that emerin is localized to the RBC plasma membrane and regulates the localization of other membrane proteins involved in actin branching and cytoskeletal dynamics. Additionally, we find that loss of Emd in mice results in decreased RBC corpuscular volume and hemoglobin content in both sexes, as well as a male-specific increase in RBC number and hematocrit, consistent with other male-dominated EMD phenotypes. Along with decreased RBC size, we observed a reduction in the rate of osmotic lysis in Emd KO animals, particularly males. We found that human EMD mutations also have a statistically significant association with RBC phenotypes, namely MCV. Individuals with emerin-related Emery-Dreifuss muscular dystrophy (EDMD) also demonstrate a mild yet consistent RBC phenotype according to patient CBC data. Together, these data suggest that emerin can have cell-specific localization and functions independent of its canonical repertoire in nucleated cells.

cell biology↗

bioRxiv2024

SUV39H1 mediated regulation of KLF4 and KDM4A coordinate smooth muscle cell phenotypic plasticity

BackgroundReversible DNA methylation contributes to the phenotypic plasticity of vascular smooth muscle cells (VSMCs). This plasticity contributes to vascular growth remodeling, but also underlies cardiovascular pathologies, including intimal hyperplasia. We investigated the role of SUV39H1, a histone methyltransferase that generates the H3K9me3 repressive epigenetic mark, in VSMC plasticity MethodsWe applied knockdown, qPCR, western blotting, chromatin immunoprecipitation (ChIP) assays, and RNA-Seq in human coronary artery SMCs (hCASMCs), and murine carotid ligation to determine the role of SUV39H1 in VSMC plasticity. ResultsExpression of SUV39H1 and the H3K9me3 mark it generates increase, whereas the cognate H3K9me3 demethylase KDM4A decreases, over time during the progression of murine intimal hyperplasia following carotid artery ligation, with marked elevation of SUV39H1 and H3K9me in the neointima. SUV39H1 knockdown induced contractile genes and contractility while decreasing migration and proliferation in hCASMCs. Transcriptomic analysis confirmed that SUV39H1 promotes SMC dedifferentiation. SUV39H1 knockdown revealed that SUV39H1 promotes KLF4 upregulation by increasing KLF4 mRNA stability. PDGF-BB induced SUV39H1 expression and SUV39H1-dependent H3K9me3 modification of contractile gene promoters in hCASMC. SUV39H1 knockdown reduced the repressive H3K9me3 and 5mC marks but increased the activating H3K27Ac mark at these promoters. SUV39H1 knockdown also increased expression of KDM4A and its binding to contractile promoters, suggesting an opposing regulatory relationship between the writer and eraser of H3K9me3. ConclusionsWe identify SUV39H1 as an epigenetic regulator that promotes VSMC dedifferentiation by stabilizing KLF4 expression and by altering chromatin state. We report SUV39H1-dependent dynamic regulation of the repressive H3K9me3 mark at contractile gene promoters, and opposing regulation of the enzymes that write (SUV39H1) and erase (KDM4A) these marks during VSMC phenotypic switching. These studies suggest that coordinate regulation of both histone and DNA methylation contribute to VSMC phenotypic plasticity. HighlightsO_LIThe histone methyl transferase SUV39H1 is differentially regulated in VSMC phenotypic switching in culture and in vascular remodeling. SUV39H1 and the H3K9me3 mark it generates increase, whereas the cognate H3K9me3 eraser KDM4A decreases, during the progression of murine intimal hyperplasia. C_LIO_LISUV39H1 promotes PDGF-induced VSMC de-differentiation, stabilizing KLF4 mRNA. SUV39H1 opposes VSMC contractility and promotes proliferation and migration. C_LIO_LIPDGF-BB induces SUV39H1-dependent H3K9me3 marks at VSMC contractile gene promoters, and SUV39H1 loss of function alters multiple marks that govern chromatin accessibility at these promoters, with opposing effects on the repressive H3K9me3 and 5mC and activating H3K27Ac marks. C_LIO_LISUV39H1 generates H3K9me3 marks that are associated with silenced heterochromatin. We note dynamic regulation of this mark at VSMC contractile gene promoters, and opposing regulation of the enzymes that write (SUV39H1) and erase (KDM4A) these marks during VSMC phenotypic switching. C_LI

cell biology↗

bioRxiv2022

Bone marrow age dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to [~]70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin {beta}3 resulting in increased tumor necrosis factor [TNF]- signaling. In turn, TNF signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin {beta}3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies. Graphical abstractAge of BM-derived monocytes/macrophages determines clonality of SMC lineage in the atherosclerotic plaque. Atherogenesis is depicted in a young (a) or aged (b) host. Aged monocytes/macrophages have decreased levels of the epigenetic regulator TET2, leading to reduction of the 5-hydroxymethylcytosine (5hmC) mark on the Itgb3 promoter. The resulting low integrin {beta}3 levels in aged monocytes/macrophages induces high TNF- levels, facilitating recruitment and expansion of multiple SMC progenitors (polyclonality) in the atherosclerotic plaque and worse disease burden. In contrast, the young control is characterized by mono/oligoclonal SMC expansion in a smaller plaque. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/476756v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12f7090org.highwire.dtl.DTLVardef@186ff92org.highwire.dtl.DTLVardef@1f4da69org.highwire.dtl.DTLVardef@2f509c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗