Department of Biological Sciences, Indian Institute of Science Education and Research (IISER)-Mohali, Knowledge City, Sector 81, SAS Nagar 140306, India.
TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research (TIFR) Hyderabad, 36/P, Gopanpally Village, Serilingampally Mandal, Hyderabad 500046, India.
Cell Rep. 2020 Oct 27;33(4):108302. doi: 10.1016/j.celrep.2020.108302.
The mechanisms that guide the clonally stable random mono-allelic expression of autosomal genes remain enigmatic. We show that (1) mono-allelically expressed (MAE) genes are assorted and insulated from bi-allelically expressed (BAE) genes through CTCF-mediated chromatin loops; (2) the cell-type-specific dynamics of mono-allelic expression coincides with the gain and loss of chromatin insulator sites; (3) dosage of MAE genes is more sensitive to the loss of chromatin insulation than that of BAE genes; and (4) inactive alleles of MAE genes are significantly more insulated than active alleles and are de-repressed upon CTCF depletion. This alludes to a topology wherein the inactive alleles of MAE genes are insulated from the spatial interference of transcriptional states from the neighboring bi-allelic domains via CTCF-mediated loops. We propose that CTCF functions as a typical insulator on inactive alleles, but facilitates transcription through enhancer-linking on active allele of MAE genes, indicating widespread allele-specific regulatory roles of CTCF.
指导常染色体基因克隆稳定随机单等位基因表达的机制仍然神秘莫测。我们表明：(1) 单等位基因表达(MAE)基因通过 CTCF 介导的染色质环与双等位基因表达(BAE)基因进行分类和隔离；(2) 单等位基因表达的细胞类型特异性动力学与染色质绝缘子位点的获得和丢失相吻合；(3) MAE 基因的剂量对染色质绝缘的丢失比 BAE 基因更敏感；(4) MAE 基因的失活等位基因比活性等位基因受到更好的隔离，并且在 CTCF 耗竭时被去抑制。这暗示了一个拓扑结构，其中 MAE 基因的失活等位基因通过 CTCF 介导的环与相邻双等位基因区域的转录状态的空间干扰隔离开来。我们提出 CTCF 作为失活等位基因的典型绝缘子发挥作用，但通过 MAE 基因的活性等位基因的增强子连接促进转录，表明 CTCF 具有广泛的等位基因特异性调控作用。
