Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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ATAC-Seq analysis of LYN deficient HS-5 stroma cells

ABSTRACT: LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient stroma cells. These cells were analyzed in a Multi-Omic approach, including ATAC-Seq analysis of adapted epigenetic regulations.

INSTRUMENT(S): 454 GS FLX

ORGANISM(S): Homo sapiens

SUBMITTER: Ali Abdallah

PROVIDER: E-MTAB-12531 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Rationale: Monocytes are key effectors of the mononuclear phagocyte system (MPS), playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into two major subsets termed conventional (cMo) and patrolling (pMo) monocytes but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology, however LYN’s role in regulating specific monocyte subset homeostasis has not been investigated. Objective: We sought to comprehensively profile monocytes in order to elucidate the underlying heterogeneity within monocytes and dissect how Lyn deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis. Methods and Results: CyTOF analysis of monocyte subsets and signaling pathway activation patterns in cMos and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described. Lyn deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN’s role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of Lyn-deficient pMos. Furthermore, single cell RNA sequencing revealed marked perturbations in the gene expression profiles of Lyn-/- monocytes with upregulation of genes involved in pMo development, survival, and function. Lyn deficiency also led to a significant increase in aorta-associated pMos and protected Ldlr-/- mice from high-fat diet induced atherosclerosis. Conclusions: Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.

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ATAC-Seq analysis of LYN deficient HS-5 stroma cells

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