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
复制标题
DOI：
10.1186/s13072-019-0297-2
复制
发表时间：
2019-08-09
影响因子：
3.9
通讯作者：
Pavan, William J.
中科院分区：
文献类型：
--
作者：
Fufa, Temesgen D.;Baxter, Laura L.;Pavan, William J.
MAPK/ERK信号通路是许多细胞过程的重要调节因子，这些细胞过程对正常发育和癌症进展至关重要。虽然我们对MAPK/ERK信号从细胞膜到细胞核的传递了解很多，但调控MAPK信号下游基因表达的转录和表观遗传机制尚未完全阐明。本研究采用综合表观基因组分析方法，探讨了MAPK/ERK通路抑制对501mel黑色素瘤细胞整体转录组、活性染色质景观和蛋白质- dna相互作用的影响。用小分子MEK抑制剂AZD6244处理这些细胞会导致色素沉着过度，广泛的基因表达改变，包括与色素沉着相关的基因改变，以及与活性染色质标记H3K27ac相关的转录不同调控区域的广泛表观基因组重编程。AZD6244处理后H3K27ac区域乙酰化差异的调控区域富含ETV/ETS和ATF家族成员以及谱系决定因子MITF和SOX10的转录因子结合基元。h3k27ac密集增强子簇被称为超级增强子，显示出类似的转录因子基序富集，此外，这些超级增强子与编码MITF、SOX10和ETV/ETS蛋白的基因相关。随着活性增强子的全基因组重置，MEK抑制也导致SOX10在整个基因组中广泛募集，包括在h3k27ac标记的增强子上增加SOX10的结合密度。重要的是，这些由H3K27ac标记并由SOX10占据的MEK抑制剂响应性增强子位于黑素细胞谱系特异性和色素沉着基因附近，并且重叠了许多与色素沉着和黑色素瘤表型相关的人类snp，突出了位于这些区域内的变异，以便在未来的研究中优先考虑。这些结果揭示了MEK抑制下501mel细胞黑素细胞色素沉着和发育转录程序再激活的表观遗传重编程，并提示MEK- sox10轴广泛参与这些过程的调控。这里发现的动态染色质变化为进一步分析色素沉着和黑素细胞相关疾病中调控MAPK通路的分子机制提供了丰富的基因组资源。
Background 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. Results 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. Conclusions 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.