MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells.

MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells.

Publication date: Aug 09, 2019

The MAPK/ERK signaling pathway is an essential regulator of numerous cell processes that are crucial for normal development as well as cancer progression. While much is known regarding MAPK/ERK signal conveyance from the cell membrane to the nucleus, the transcriptional and epigenetic mechanisms that govern gene expression downstream of MAPK signaling are not fully elucidated.

This study employed an integrated epigenome analysis approach to interrogate the effects of MAPK/ERK pathway inhibition on the global transcriptome, the active chromatin landscape, and protein-DNA interactions in 501mel melanoma cells. Treatment of these cells with the small-molecule MEK inhibitor AZD6244 induces hyperpigmentation, widespread gene expression changes including alteration of genes linked to pigmentation, and extensive epigenomic reprogramming of transcriptionally distinct regulatory regions associated with the active chromatin mark H3K27ac. Regulatory regions with differentially acetylated H3K27ac regions following AZD6244 treatment are enriched in transcription factor binding motifs of ETV/ETS and ATF family members as well as the lineage-determining factors MITF and SOX10. H3K27ac-dense enhancer clusters known as super-enhancers show similar transcription factor motif enrichment, and furthermore, these super-enhancers are associated with genes encoding MITF, SOX10, and ETV/ETS proteins. Along with genome-wide resetting of the active enhancer landscape, MEK inhibition also results in widespread SOX10 recruitment throughout the genome, including increased SOX10 binding density at H3K27ac-marked enhancers. Importantly, these MEK inhibitor-responsive enhancers marked by H3K27ac and occupied by SOX10 are located near melanocyte lineage-specific and pigmentation genes and overlap numerous human SNPs associated with pigmentation and melanoma phenotypes, highlighting the variants located within these regions for prioritization in future studies.

These results reveal the epigenetic reprogramming underlying the re-activation of melanocyte pigmentation and developmental transcriptional programs in 501mel cells in response to MEK inhibition and suggest extensive involvement of a MEK-SOX10 axis in the regulation of these processes. The dynamic chromatin changes identified here provide a rich genomic resource for further analyses of the molecular mechanisms governing the MAPK pathway in pigmentation- and melanocyte-associated diseases.

Fufa, T.D., Baxter, L.L., Wedel, J.C., Gildea, D.E., Program, NISC Comparative. Sequencing., Loftus, S.K., and Pavan, W.J. MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells. 23711. 2019 Epigenetics Chromatin (12):1.

Concepts Keywords
Acetylated BRAFV600E mutant melanoma
ATF Hyperpigmentation
Chromatin Branches of biology
DNA Biochemistry
Enhancer Gene expression
Enhancers Transcription factors
Epigenetic Signal transduction
Epigenetics Posttranslational modification
Epigenome Cell signaling
ERK H3K27ac
ETV SOX10
Genome Microphthalmia-associated transcription factor
Hyperpigmentation Enhancer
MAPK
MEK
Melanocyte
Melanoma
Membrane
MITF
Motif
Mutant
Nucleus
Phenotypes
Protein
Regulatory Regions
Small Molecule
SNPs
Transcription Factor
Transcriptome

Semantics

Type Source Name
gene UNIPROT MITF
gene UNIPROT GDNF
gene UNIPROT MARK1
disease MESH hyperpigmentation
pathway BSID Gene Expression
disease DOID cancer
disease MESH cancer
disease MESH development
gene UNIPROT EPHB2
pathway BSID Melanoma
disease DOID melanoma
gene UNIPROT BRAF
disease MESH melanoma
gene UNIPROT SOX10

Original Article

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