摘要
真核基因表达调控是发生在细胞核内的一个复杂而精细的过程,对维持细胞乃至机体的正常生理功能起到至关重要的作用。其中,染色质水平的调控作为真核基因表达调控的一种重要方式日益受到人们的重视。核基质结合蛋白是一类重要的真核基因转录调控因子,它们定位到细胞核内的核基质结构上,与大量调控相关的转录因子和酶类形成复合物,并参与基因的活化或抑制。目前已经发现的核基质结合蛋白有很多,包括SAF-A, Cux/CDP, SATB1, SATB2等。其中,SATB1和SATB2是属于SATB家族的一类经典的核基质结合蛋白,它们可以结合到基因调控序列的AT富含区从而调控染色质的结构。
珠蛋白基因簇的表达调控是研究真核基因转录调控的经典模型。人珠蛋白基因簇由上游的一系列超敏位点组成的基因座控制区(locus control region, LCR)和下游的胚胎期(ε)、胎儿期(γ)和成年期(β)珠蛋白基因组成。在珠蛋白基因簇活化时上游基因座控制区会与下游活性基因空间靠近形成活性染色质中心。已有研究表明SATB1在人β珠蛋白基因簇上有多个结合位点,并转录调节胚胎期珠蛋白基因的表达以及通过促进结合位点间的靠近来调控β珠蛋白基因簇的整体空间结构。
在本研究中,我们利用人γ珠蛋白基因启动子的AT富含区作为探针,捕获到核基质结合蛋白SATB2的结合。这段序列曾被发现具有结合SATB1的能力,但这种结合未在体内证实。进一步对SATB2的表达进行研究发现其在K562细胞和人脐血造血干细胞红系分化期间持续表达,并主要在小鼠发育早期阶段表达。
通过体内和体外的结合实验,我们证实SATB2可以特异地结合在Gγ和Aγ珠蛋白基因的启动子上游区域且前者结合力较强。通过将Gγ和Aγ珠蛋白基因启动子区构建到报告基因的载体中进行实验,我们发现SATB2可以反式增强Gγ和Aγ启动子的活性。我们在K562细胞中分别过表达和干扰了SATB2蛋白,发现SATB2对γ珠蛋白基因起激活的作用。我们还检测了组蛋白修饰和RNA聚合酶Ⅱ的募集,发现染色质结构的变化与基因表达变化是一致的。我们进一步在人脐血来源的造血祖细胞中过表达和干扰了SATB2蛋白并诱导其向红系分化,证实了SATB2对γ珠蛋白基因的激活作用。
我们进一步研究SATB2激活γ珠蛋白基因的分子机制。我们发现组蛋白乙酰化酶PCAF可以与SATB2相互作用并促进其反式激活能力,并被SATB2募集到γ珠蛋白基因启动子上。通过SATB2的串联亲和纯化实验我们发现SATB2与SATB1通过各自的PDZ蛋白区域相互作用,提示二者可能协同促进β珠蛋白基因簇的活性空间构象的组织。染色质构象捕获技术(chromosome conformation capture,3C)发现,SATB2可以促进Gγ和Aγ基因启动子区域的空间靠近,但并不影响其它元件所在染色质区域的空间靠近,说明SATB1和SATB2两个蛋白在β珠蛋白基因簇的调控中具有分工。ChIP-3C的实验证明这种空间靠近是SATB2蛋白介导的。进一步的蛋白质免疫共沉淀实验证明SATB2蛋白具有分子间自身相互作用,这种自我相互作用可能就是SATB2介导染色质靠近的原因。
综上所述,我们的研究说明在红系细胞中,SATB2通过结合在Gγ和Aγ珠蛋白基因启动子区的AT富含区上,募集组蛋白乙酰化酶,促进丫珠蛋白基因的表达和染色质的活化,并促进Gγ和Aγ珠蛋白基因启动子区的空间靠近。本研究进一步丰富了SATB1介导的MAR元件空间靠近的结构,同时也为深入了解β珠蛋白基因簇活性染色质中心的结构提供了实验依据。
Eukaryotic gene transcriptional regulation is a complex and intricate nuclear process that is essential for normal physiological functions. Regulation to the chromatin structure presents an important level of eukaryotic gene regulation, and has attracted an ever-increasing attention. MAR binding proteins are important eukaryotic transcriptional regulators that specifically associate nuclear matrix and related transcriptional factors and enzymes, and many of them have been confirmed to globally affect gene activation and repression. Multiple MAR binding proteins have been found, including SAF-A, Cux/CDP, SATB1and SATB2. Notably, both SATB1and SATB2belong to the SATB protein family, and bind to AT-rich sequences for the regulation of chromatin structure.
Globin gene locus is a typical model for studying eukaryotic gene regulation. Human β-globin locus is composed of upstreaming locus control region (LCR) with multiple hypersensitive sites, and downstreaming globin genes including the embryonic (ε), fetal (γ) and adult (β) globin genes. When β-globin gene cluster is activated, LCR and the active globin genes get in proximity and form active chromatin hub (ACH). We previously reported that SATB1binds to P-globin gene cluster at multiple sites, regulates chromatin conformation of the cluster through facilitating proximities of its binding sites, and specifically affects the expression of e-globin gene.
In this study, we used AT-rich sequence in y-globin gene promoter as the probe, and captured MAR binding protein SATB2. This AT-rich sequence was reported to bind to SATB1in vitro, but not in vivo. We further identified that SATB2expressed consistently during the erythroid differentiation of K562cells and human umbilical cord CD34+cells, and that mSATB2expressed primarily in early murine developmental stage.
Using ChIP and EMSA experiments, we proved that SATB2specifically bound to Gγ and Aγ-globin promoters with a preference to the former. SATB2trans-activated Gγ and Ay-globin promoters in luciferase reporter assay. Overexpression and knockdown experiments in K562cells also showed that SATB2promoted y-globin expression. Histone modifications and RNA polymerase II recruitment statues at γ-globin promoter are found consistent with alterations of y-globin expression. Further, we overexpressed and knockdown SATB2in human umbilical cord derived primary erythroid cells respectively, activation of y-globin by SATB2was also detected.
Further studies on molecular mechanisms of SATB2facilitated y-globin activation identified histone acetylase PCAF as a SATB2associated protein that promotes the activity of SATB2. PCAF can also be recruited by SATB2to y-globin gene promoter. Tandom affinity purification assay was then performed, and we found that SATB2interacted with SATB1through their PDZ domains. This indicates that they cooperate in the regulation of chromatin conformation of β-globin gene cluster. Using chromosome conformation capture assay, we continued to identify that SATB2promoted physical proximity of Gy and Ay-globin promoter regions without influencing proximities of other regulatory elements. The observation argued that SATB1and SATB2differentiate in their particular roles in higher-order chromatin organization and regulation of P-globin gene cluster. ChIP-3C assay shows that this proximity is mediated by SATB2. Further co-IP assay shows that SATB2interacts with itself, provides a possibility that self-association of SATB2mediates y-globin gene specific chromatin association.
In summary, our study shows that in erythroid cells, SATB2binds to the AT-rich regions of the Gy and Ay-globin gene promoters, facilitates their proximity and activates their chromatin structure by recruiting histone acetylase, and eventually promotes y-globin gene expression. This study further enriches SATB1mediated "inter-MAR association" structure, and provides experimental evidence for further understanding active chromatin hub of P-globin gene cluster.
引文
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