本期文章：《自然—细胞生物学》：Online/在线发表

美国西奈山伊坎医学院Emily Bernstein、Dan Filipescu团队的最新研究表明，MacroH2A通过协调染色质环来阻碍黑色素瘤癌症相关成纤维细胞中炎症基因的表达。相关论文于2023年8月21日发表在《自然-细胞生物学》杂志上。

使用免疫功能正常的黑色素瘤小鼠模型，研究人员发现与野生型小鼠相比，没有macroH2A变异的小鼠表现出肿瘤负荷增加。macroH2A缺陷肿瘤会积累免疫抑制单核细胞并导致功能性细胞毒性T细胞耗竭，这些特征与抗肿瘤反应受损一致。单细胞和空间转录组学表明肿瘤区室神经嵴谱系的去分化增加，以及macroH2A丢失后癌症相关成纤维细胞的频率和活化增加。

从机制上讲，macroH2A缺陷癌症相关成纤维细胞由于其炎症基因被诱导高表达而显示出增加的髓系化学诱导活性，这是通过增加其启动子区染色质环进而获得H3K27ac来实现。总之，该研究通过调节肿瘤基质中的染色质结构揭示了macroH2A变异的肿瘤抑制作用，对人类黑色素瘤的治疗具有潜在意义。

据悉，已有研究表明MacroH2A可在黑色素瘤和其他癌症中发挥抑制肿瘤的功能，但其在肿瘤微环境中的作用知之甚少。

附：英文原文

Title: MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping

Author: Filipescu, Dan, Carcamo, Saul, Agarwal, Aman, Tung, Navpreet, Humblin, tienne, Goldberg, Matthew S., Vyas, Nikki S., Beaumont, Kristin G., Demircioglu, Deniz, Sridhar, Subhasree, Ghiraldini, Flavia G., Capparelli, Claudia, Aplin, Andrew E., Salmon, Hlne, Sebra, Robert, Kamphorst, Alice O., Merad, Miriam, Hasson, Dan, Bernstein, Emily

Issue&Volume: 2023-08-21

Abstract: MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic Tcells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma.

DOI: 10.1038/s41556-023-01208-7