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Cell Rep. 2017 Apr 25;19(4):875-889. doi: 10.1016/j.celrep.2017.03.078.

Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression.

Author information

1
Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA.
2
Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
3
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Boston University, Boston, MA 02215, USA.
6
Division of Cancer Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
7
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Division of Internal Medicine, Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10
Weizmann Institute of Science, Rehovot 761001, Israel.
11
Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Cancer Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Institute for Health Transformation, The University of Texas System, Austin, TX 78701, USA. Electronic address: lchin@utsystem.edu.
12
Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA; Department of Computer Science, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA. Electronic address: jason.ernst@ucla.edu.
13
Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: krai@mdanderson.org.

Abstract

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.

KEYWORDS:

CBP; ChIP-seq; DUSP5; HDAC; chromatin state; epigenome; histone modifications; melanoma

PMID:
28445736
PMCID:
PMC5473172
DOI:
10.1016/j.celrep.2017.03.078
[Indexed for MEDLINE]
Free PMC Article

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