Browsing by Author "Lewis, Tylor R"

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    Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.
    (Scientific reports, 2021-01-26) Maddala, Rupalatha; Gao, Junyuan; Mathias, Richard T; Lewis, Tylor R; Arshavsky, Vadim Y; Levine, Adriana; Backer, Jonathan M; Bresnick, Anne R; Rao, Ponugoti V
    S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 (-/-) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 (-/-) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4 (-/-) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4 (-/-) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.
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    Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.
    (Cell research, 2023-07) Pan, Christopher C; Maeso-Díaz, Raquel; Lewis, Tylor R; Xiang, Kun; Tan, Lianmei; Liang, Yaosi; Wang, Liuyang; Yang, Fengrui; Yin, Tao; Wang, Calvin; Du, Kuo; Huang, De; Oh, Seh Hoon; Wang, Ergang; Lim, Bryan Jian Wei; Chong, Mengyang; Alexander, Peter B; Yao, Xuebiao; Arshavsky, Vadim Y; Li, Qi-Jing; Diehl, Anna Mae; Wang, Xiao-Fan
    Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.