Dissecting the myeloid lineage in human gliomas

Identification: Han, Claudia


Description

Dissecting the myeloid lineage in human gliomas
 
Claudia Z. Han1, Sascha H. Duttke1, Sebastian Preissl2, Johannes C.M. Schlachetzki1, Alexi Nott1, Zhengyu Ouyang1, Nicole G. Coufal3, Bing Ren2,4, Christopher K. Glass1,5
1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; 2Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; 3Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; 4Ludwig Institute for Cancer Research, La Jolla, CA, USA; 5Department of Medicine, University of California, San Diego, La Jolla, CA, USA
 
The immune cell composition of the tumor microenvironment can be a decisive factor for tumor pathogenesis. Gliomas are tumors that develop from the glial cells of the brain and spinal cord and make up to 30% of all brain tumors. In gliomas, microglia and infiltrating macrophages can compose up to 30 to 50% of total tumor-associated cells. Increased CD68 staining, a marker of monocytes and macrophages, in adult gliomas is positively associated with histological tumor grade. Despite sharing common properties with other tissue resident macrophages, recent work has demonstrated that microglia express hundreds of genes at higher levels compared to other tissue macrophage subsets. The expression of these microglia enriched genes are influenced by the central nervous system environment. The integration of environmentally derived signals with gene regulation occurs at the genomic level on regulatory DNA sequences termed enhancers. Enhancers regulate the specificity and amplitude of gene expression and are activated through the binding of signal-dependent transcription factors. Despite the accumulated evidence substantiating a critical role for microglia and infiltrating macrophages in gliomagenesis, little is known is about the molecular mechanisms driving microglial contribution to tumor growth and whether microglia are therapeutic targets in both low- and high-grade gliomas. By integrating transcriptome analysis with chromatin and enhancer states, we seek to complete a comprehensive comparative analysis of the enhancer repertoires and corresponding epigenetic landscapes between the myeloid populations of these tumors, with the ultimate goal of deciphering how the tumor microenvironment reprograms the transcription factor network in microglia to generate tumor-promoting cells.
 

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