11 种肿瘤类型癌症转变过程中的表观遗传调控

2023-11-17 10:15

虽然人们已经研究了基因对致癌转变的影响，但对表观遗传驱动因素的了解仍然较少。在这里，我们利用225个样本的单核染色质可及性数据（利用单核转座酶可及染色质检测法）和206个样本的匹配单细胞或单核RNA序列表达数据，构建了泛癌症表观遗传学和转录组图谱。通过富集可访问染色质区域、转录因子基序和调控子，我们从每个平台分析了100多万个细胞，从而确定了与癌症转变相关的表观遗传驱动因素。

SCI

15 November 2023

Epigenetic regulation during cancer transitions across 11 tumour types

（Nature, if=64.8）

Terekhanova NV, Karpova A, Liang WW, Strzalkowski A, Chen S, Li Y, Southard-Smith AN, Iglesia MD, Wendl MC, Jayasinghe RG, Liu J, Song Y, Cao S, Houston A, Liu X, Wyczalkowski MA, Lu RJ, Caravan W, Shinkle A, Naser Al Deen N, Herndon JM, Mudd J, Ma C, Sarkar H, Sato K, Ibrahim OM, Mo CK, Chasnoff SE, Porta-Pardo E, Held JM, Pachynski R, Schwarz JK, Gillanders WE, Kim AH, Vij R, DiPersio JF, Puram SV, Chheda MG, Fuh KC, DeNardo DG, Fields RC, Chen F, Raphael BJ, Ding L.
Corresponding: lding@wustl.edu

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

染色质可及性在调节基因表达和细胞特性方面至关重要，可及性的改变与癌症的发生、发展和转移有关。虽然人们已经研究了基因对致癌转变的影响，但对表观遗传驱动因素的了解仍然较少。在这里，我们利用 225 个样本的单核染色质可及性数据（利用单核转座酶可及染色质检测法）和 206 个样本的匹配单细胞或单核 RNA 序列表达数据，构建了泛癌症表观遗传学和转录组图谱。通过富集可访问染色质区域、转录因子基序和调控子，我们从每个平台分析了 100 多万个细胞，从而确定了与癌症转变相关的表观遗传驱动因素。一些表观遗传驱动因素出现在多种癌症中（例如，ABCC1和VEGFA的调控区；GATA6和FOX家族基团），而另一些则具有癌症特异性（例如，FGF19、ASAP2和EN1的调控区以及PBX3基团）。在表观遗传改变的通路中，TP53、缺氧和 TNF 信号与癌症的发生有关，而雌激素反应、上皮-间质转化和顶端连接则与转移转化有关。此外，我们还揭示了增强子可及性与基因表达之间的显著相关性，并发现了表观遗传和基因驱动之间的合作。该图谱为进一步研究癌症转化过程中的表观遗传动态提供了基础。