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破坏 CTCF-YY1 依赖的人乳头瘤病毒基因组环化可激活分化诱导的病毒癌基因转录。

Disruption of CTCF-YY1-dependent looping of the human papillomavirus genome activates differentiation-induced viral oncogene transcription.

机构信息

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.

School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom.

出版信息

PLoS Biol. 2018 Oct 25;16(10):e2005752. doi: 10.1371/journal.pbio.2005752. eCollection 2018 Oct.

DOI:10.1371/journal.pbio.2005752
PMID:30359362
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6219814/
Abstract

The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to support virus replication. We report that the chromatin-organising CCCTC-binding factor (CTCF) promotes the formation of a chromatin loop in the HPV genome that epigenetically represses viral enhancer activity controlling E6/E7 expression. CTCF-dependent looping is dependent on the expression of the CTCF-associated Yin Yang 1 (YY1) transcription factor and polycomb repressor complex (PRC) recruitment, resulting in trimethylation of histone H3 at lysine 27. We show that viral oncogene up-regulation during cellular differentiation results from YY1 down-regulation, disruption of viral genome looping, and a loss of epigenetic repression of viral enhancer activity. Our data therefore reveal a key role for CTCF-YY1-dependent looping in the HPV life cycle and identify a regulatory mechanism that could be disrupted in HPV carcinogenesis.

摘要

致癌型人类乳头瘤病毒（HPV）的复杂生命周期始于未分化的基底上皮角质形成细胞，其中 E6 和 E7 癌基因的表达受到限制。在上皮分化过程中，E6/E7 转录通过未知机制增加，以驱动支持病毒复制所需的细胞增殖。我们报告说，染色质组织因子 CCCTC-结合因子（CTCF）促进 HPV 基因组中染色质环的形成，这种染色质环通过表观遗传抑制控制 E6/E7 表达的病毒增强子活性。CTCF 依赖性环化依赖于 CTCF 相关 Yin Yang 1（YY1）转录因子的表达和多梳抑制复合物（PRC）的募集，导致组蛋白 H3 在赖氨酸 27 处的三甲基化。我们表明，细胞分化过程中病毒癌基因的上调是由于 YY1 下调、病毒基因组环化中断以及病毒增强子活性的表观遗传抑制丧失所致。因此，我们的数据揭示了 CTCF-YY1 依赖性环化在 HPV 生命周期中的关键作用，并确定了一种可能在 HPV 致癌作用中被破坏的调节机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff73/6219814/b31c38b2bdb5/pbio.2005752.g008.jpg
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