Cohesin and CTCF differentially regulate spatiotemporal runxl expression during zebrafish development
Cohesin and CTCF differentially regulate spatiotemporal runxl expression during zebrafish development
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DOI：
10.1016/j.bbagrm.2013.11.007
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发表时间：
2014-01-01
影响因子：
4.7
通讯作者：
Horsfield, Julia A.
中科院分区：
文献类型：
--
作者：
Marsman, Judith;O'Neill, Adam C.;Horsfield, Julia A.
Runx1是决定性造血所必需的转录因子。在所有脊椎动物中，Runxl基因是从两个启动子转录的：一个近端启动子（P2）和一个远端启动子（P1）。我们之前发现runx1在斑马鱼胚胎中特定造血细胞群中的表达依赖于内聚素。本研究表明，斑马鱼runxl在P1和P2启动子处以及P1和P2之间的内含子内直接被黏结蛋白和CCCTC结合因子（CTCF）结合。内聚素启动后外侧中胚层runx1的表达并影响启动子的使用，而CTCF抑制其在尾芽新生细胞中的表达。黏结蛋白和CTCF的内含子结合位点与组蛋白修饰相一致，这些修饰赋予了类似增强子的特性，并且在体内实验中，两个黏结蛋白/CTCF位点表现为绝缘体。所鉴定的内聚蛋白和CTCF结合位点很可能是runx1的顺式调控元件（cre），因为它们也募集RNA聚合酶II （RNAPII）。CTCF缺失将RNAPII从两个内含子cre中排除，但没有将runx1的启动子排除。我们认为，在斑马鱼胚胎发生过程中，内聚蛋白和CTCF在runx1的调控中具有不同的功能，这些调控功能可能涉及runx1内含子CREs。内聚蛋白（而非CTCF）缺失增强了RUNX1在人白血病细胞系中的表达，表明RUNX1的调控通过进化得以保存。(C) 2013 Elsevier B.V.版权所有
Runx1 is a transcription factor essential for definitive hematopoiesis. In all vertebrates, the Runxl gene is transcribed from two promoters: a proximal promoter (P2), and a distal promoter (P1). We previously found that runx1 expression in a specific hematopoietic cell population in zebrafish embryos depends on cohesin. Here we show that zebrafish runxl is directly bound by cohesin and CCCTC binding factor (CTCF) at the P1 and P2 promoters, and within the intron between P1 and P2. Cohesin initiates expression of runx1 in the posterior lateral mesoderm and influences promoter use, while CTCF represses its expression in the newly emerging cells of the tail bud. The intronic binding sites for cohesin and CTCF coincide with histone modifications that confer enhancer-like properties, and two of the cohesin/CTCF sites behaved as insulators in an in vivo assay. The identified cohesin and CTCF binding sites are likely to be cis-regulatory elements (CREs) for runx1 since they also recruit RNA polymerase II (RNAPII). CTCF depletion excluded RNAPII from two intronic CREs but not the promoters of runx1. We propose that cohesin and CTCF have distinct functions in the regulation of runx1 during zebrafish embryogenesis, and that these regulatory functions are likely to involve runx1 intronic CREs. Cohesin (but not CTCF) depletion enhanced RUNX1 expression in a human leukemia cell line, suggesting conservation of RUNX1 regulation through evolution. (C) 2013 Elsevier B.V. All rights reserved.