Genome-wide chromatin occupancy of transcription factor TBX2 in luminal breast cancer cells

Here we demonstrate a previously unknown mechanism of TBX2-mediated gene repression in breast tumours, whereby TBX2 physically interacts with CoREST-associated proteins LSD1, HDAC1 and the ZNF217 oncogene. Through Chromatin Immunoprecipitation sequencing (ChIP-seq) we find that while over 80% of TBX2 binding sites are concentrated at promoters, these regions show remarkably no enrichment for the T-box element; rather TBX2-bound regions are biased toward a small number of non-T-box motifs, with the most abundant being Specificity Protein 1 (Sp1), EGR1 and Nuclear Transcription Factor Y (NF-Y). Furthermore, we uncover that Sp1 is crucial for recruitment of TBX2 to the NDRG1 promoter and subsequent repression of this gene. We also observe that ZNF217 cooccupies approximately 30% of TBX2-bound sites, a number of which contain RCOR1 and exhibit upregulation of the associated transcripts following disruption of TBX2/CoREST function. Overall these data highlight a novel potential therapeutic opportunity whereby poor-prognosis, TBX2 overexpressing breast tumours may be pharmacologically exploited by targeting the CoREST-dependent gene repression network, to recover normal growth control. Examination of TBX2 genome-wide occupancy in MCF-7 cells by ChIP-seq

本研究揭示了乳腺癌中TBX2介导的基因沉默这一此前未被报道的全新机制：TBX2可与CoREST相关蛋白赖氨酸特异性去甲基化酶1（LSD1）、组蛋白去乙酰化酶1（HDAC1）以及癌基因锌指蛋白217（ZNF217）发生物理相互作用。通过染色质免疫沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）分析，我们发现尽管超过80%的TBX2结合位点富集于启动子区域，但此类区域并未显著富集T-box元件；相反，TBX2结合区域更偏向于少量非T-box基序，其中丰度最高的为特异性蛋白1（Specificity Protein 1, Sp1）、早期生长应答蛋白1（EGR1）以及核转录因子Y（Nuclear Transcription Factor Y, NF-Y）。此外，本研究证实Sp1对于TBX2被招募至NDRG1启动子区域并后续沉默该基因发挥关键作用。我们同时观察到，ZNF217共同占据了约30%的TBX2结合位点，其中部分位点包含RCOR1，且在TBX2/CoREST功能受到干扰后，相关转录本的表达会上调。综上，本研究数据揭示了一种极具潜力的全新治疗策略：对于预后不良且TBX2过表达的乳腺癌，可通过靶向CoREST依赖的基因沉默网络，恢复细胞正常生长调控。通过ChIP-seq检测MCF-7细胞内TBX2的全基因组结合占据情况