Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma
Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma
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DOI：
10.1038/s41418-019-0333-6
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发表时间：
2020-01-01
影响因子：
12.4
通讯作者：
Davidson, Irwin
中科院分区：
文献类型：
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作者：
Laurette, Patrick;Coassolo, Sebastien;Davidson, Irwin
BRAF的体细胞致癌突变加上PTEN的失活构成了基因组改变的频繁组合，驱动人类黑色素瘤的发展。基因工程改造的小鼠在他莫昔芬治疗后在黑素细胞中条件性表达致癌Braf（V600 E）和BMPten，迅速发展为黑色素瘤。虽然早期黑色素瘤包括黑色素沉着的Mitf和Dct表达细胞，这些和其他黑色素细胞身份基因的表达在后期肿瘤中丢失，显示出去分化神经嵴型细胞的组织学和分子特征。黑素细胞身份基因显示活性染色质标记和RNA聚合酶II的丢失和异染色质标记的获得，表明肿瘤进展过程中的表观遗传重编程。然而，培养中生长的晚期肿瘤细胞重新表达Mitf，黑素细胞标志物和Mitf与Sox 10共同调节了大量对其生长至关重要的基因。在该黑色素瘤模型中，SWI/SNF复合物的催化Brgl（Smarca 4）亚基和NuRF复合物的支架Bptf亚基的体细胞失活延迟了肿瘤形成并解除了正常肿瘤细胞生长所必需的大的和重叠的基因表达程序的调节。此外，我们发现，Brgl和Bptf协同调节许多基因与Mitf和Sox 10。这些转录因子和染色质重塑复合物共同协调小鼠黑色素瘤细胞中的必需基因表达程序。
Somatic oncogenic mutation of BRAF coupled with inactivation of PTEN constitute a frequent combination of genomic alterations driving the development of human melanoma. Mice genetically engineered to conditionally express oncogenic Braf(V600E) and inactivate Pten in melanocytes following tamoxifen treatment rapidly develop melanoma. While early-stage melanomas comprised melanin-pigmented Mitf and Dct-expressing cells, expression of these and other melanocyte identity genes was lost in later stage tumours that showed histological and molecular characteristics of de-differentiated neural crest type cells. Melanocyte identity genes displayed loss of active chromatin marks and RNA polymerase II and gain of heterochromatin marks, indicating epigenetic reprogramming during tumour progression. Nevertheless, late-stage tumour cells grown in culture re-expressed Mitf, and melanocyte markers and Mitf together with Sox10 coregulated a large number of genes essential for their growth. In this melanoma model, somatic inactivation that the catalytic Brgl (Smarca4) subunit of the SWI/SNF complex and the scaffolding Bptf subunit of the NuRF complex delayed tumour formation and deregulated large and overlapping gene expression programs essential for normal tumour cell growth. Moreover, we show that Brgl and Bptf coregulated many genes together with Mitf and Sox10. Together these transcription factors and chromatin remodelling complexes orchestrate essential gene expression programs in mouse melanoma cells.