Loss of ATRX, associated with DNA methylation pattern of chromosome end, impacted biological behaviors of astrocytic tumors
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Jinquan Cai1,6,*, Jing Chen2,6,*, Wei Zhang2,4,6, Pei Yang2,4,6, Chuanbao Zhang2,4,6, Mingyang Li2,4,6, Kun Yao6,7, Hongjun Wang1,6, Qingbin Li1,6, Chuanlu Jiang1,6, Tao Jiang2,3,4,5,6
1Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
2Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
3Beijing Institute for Brain Disorders Brain Tumor Center, Beijing, China
4Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
5China National Clinical Research Center for Neurological Diseases, Beijing, China
6Chinese Glioma Cooperative Group (CGCG), Beijing, China
7Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
*These authors have contributed equally to this work
Chuanlu Jiang, e-mail: [email protected]
Tao Jiang, e-mail: [email protected]
Keywords: ATRX, DNA methylation, chromosome end, MGMT, biological behaviors
Received: September 22, 2014 Accepted: April 24, 2015 Published: May 04, 2015
Loss of ATRX leads to epigenetic alterations, including abnormal levels of DNA methylation at repetitive elements such as telomeres in murine cells. We conducted an extensive DNA methylation and mRNA expression profile study on a cohort of 82 patients with astrocytic tumors to study whether ATRX expression was associated with DNA methylation level in astrocytic tumors and in which cellular functions it participated. We observed that astrocytic tumors with lower ATRX expression harbored higher DNA methylation level at chromatin end and astrocytic tumors with ATRX-low had distinct gene expression profile and DNA methylation profile compared with ATRX-high tumors. Then, we uncovered that several ATRX associated biological functions in the DNA methylation and mRNA expression profile (GEP), including apoptotic process, DNA-dependent positive regulation of transcription, chromatin modification, and observed that ATRX expression was companied by MGMT methylation and expression. We also found that loss of ATRX caused by siRNA induced apoptotic cells increasing, reduced tumor cell proliferation and repressed the cell migration in glioma cells. Our results showed ATRX-related regulatory functions of the combined profiles from DNA methylation and mRNA expression in astrocytic tumors, and delineated that loss of ATRX impacted biological behaviors of astrocytic tumor cells, providing important resources for future dissection of ATRX role in glioma.
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