Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis.,Nature Cell Biology

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Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-04-13 , DOI: 10.1038/s41556-020-0503-2
Donglim Esther Park _{1,

2} , Jingwei Cheng _{2,

3} , John P McGrath ₄ , Matthew Y Lim _{1,

5} , Camille Cushman _{1,

2} , Selene K Swanson ₆ , Michelle L Tillgren ₇ , Joao A Paulo ₅ , Prafulla C Gokhale ₇ , Laurence Florens ₆ , Michael P Washburn _{6,

8} , Patrick Trojer ₄ , James A DeCaprio _{1,

2,

3}

Affiliation

Merkel cell carcinoma (MCC)-a neuroendocrine cancer of the skin-is caused by the integration of Merkel cell polyomavirus and persistent expression of large T antigen and small T antigen. We report that small T antigen in complex with MYCL and the EP400 complex activates the expression of LSD1 (KDM1A), RCOR2 and INSM1 to repress gene expression by the lineage transcription factor ATOH1. LSD1 inhibition reduces the growth of MCC in vitro and in vivo. Through a forward-genetics CRISPR-Cas9 screen, we identified an antagonistic relationship between LSD1 and the non-canonical BAF (ncBAF) chromatin remodelling complex. Changes in gene expression and chromatin accessibility caused by LSD1 inhibition were partially rescued by BRD9 inhibition, revealing that LSD1 and ncBAF antagonistically regulate an overlapping set of genes. Our work provides mechanistic insight into the dependence of MCC on LSD1 and a tumour suppressor role for ncBAF in cancer.

中文翻译：

Merkel 细胞多瘤病毒激活 LSD1 介导的非经典 BAF 阻断以调节转化和肿瘤发生。

默克尔细胞癌 (MCC) - 一种皮肤神经内分泌癌 - 是由默克尔细胞多瘤病毒的整合和大 T 抗原和小 T 抗原的持续表达引起的。我们报道了与 MYCL 和 EP400 复合物复合的小 T 抗原通过谱系转录因子 ATOH1 激活 LSD1 (KDM1A)、RCOR2 和 INSM1 的表达以抑制基因表达。LSD1抑制在体外和体内减少MCC的生长。通过正向遗传学 CRISPR-Cas9 筛选，我们确定了 LSD1 和非经典 BAF (ncBAF) 染色质重塑复合物之间的拮抗关系。由 LSD1 抑制引起的基因表达和染色质可及性的变化部分被 BRD9 抑制所挽救，这表明 LSD1 和 ncBAF 拮抗调节一组重叠的基因。

更新日期：2020-04-24

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