Normal and Pathologic Functions of CTCF and Its Distinct Classes of DNA-targets

CTCF 的正常和病理功能及其不同类型的 DNA 靶标

基本信息

项目摘要

The first US patent issued for CTCF in October 1999 included full length cDNAs sequences coding for exceptionally conserved gene ubiquitously expressed in somatic cells from a wide range of evolutionary divergent species, including Drosophila, birds, mice, and humans. CTCF is unique multifunctional nuclear factor with multiple sequence-specificity which controls global genome architecture and many aspects of allele-specific epigenetic regulation including direct repression and/or activation of transcription, pausing-associated splicing, replication timing, long-range enhancer-promoter communications and hormone-induced silencing. Initially demonstrated by us (MCB 2004) in vitro dimerization between distinct CTCF/DNA complexes was recently shown to mediate universal site-specific intergenic, intra-chromosomal, and inter-chromosomal linking-looping in vivo through interactions between distinct classes of regulatory elements containing varying DNA sequences of CTCF-target-sites (CTSes). We discovered that sequence-specific DNA-bound CTCF-complexes are capable of dimerization in vitro which could serve in vivo to bridge different CTCF-bound sites across nuclear chromatin. Next, we have first demonstrated that upon binding to dissimilar DNA-sites CTCF can thereby function through two major mechanisms: either by direct regulation of a gene downstream of CTSes or by indirect regulation via the formation of chromatin loops stabilized upon CTCF/DNA-dimerization. that affects allele-specific relationships between the promoter, enhancer, and/or an imprinted control region (ICR) on either same or different chromosome. Dimerization of DNA-bound CTCF may potentially be at the core of its activity as a versatile chromatin-bridging and chromatin-looping agent, underlying its fundamental biological functions. The loop-forming activity of CTCF can be naturally extended to include formation of localized somatic inter-chromosome pairing sites that may acquire potential for epigenetic co-regulation through allele-specific transcription factories, DNA replication factories, 5-mC/5-hmC excisions, and DNA repair foci. Many other chromatin-anchored functions, such as the establishment of imprinting marks and their reading, X-chromosome inactivation, and apoptosis, are also regulated by CTCF. CTCF has emerged as a key facilitator of 3D organization of interphase chromatin, as well as a major player in cell proliferation control. In some cases, the loop-forming activity of CTCF was found to be accompanied/complemented by the more direct regulation of a particular gene. This mixed mode regulation is likely the most appropriate representation of a native gene regulation framework. In addition to phosphorylation and poly(ADP)rybozylation of CTCF, we also identified CTCF-interacting partner proteins, Sin3A and YB-1, which have recently gained increased attention in course of ongoing interpretation of the NGS data generated by MPS (in collaboration with Dr. B. Ren) with regard to the genomewide CTCF and CTCFL occupancy, Pol 2 initiation, transcription pausing coupled with splicing, and rewiring regulatory elements of CTCFL positive cancer cells by mobile retrotransposones with variable length tandem repeats (VNTR) affected often by a gain of CTCF site specific SNPs. Moreover, we expanded our previous studies of important CTCF activity that directly links CTCF to transcriptional machinery: the binding of CTCF to the Pol II. This novel pathway is sensitive to external signals that affect post-translational modifications of critical CTCF amino acids and provides either a mechanism for opening loop-independent transcription start sites downstream of the promoter-determined +1 site (at intron/exon sequences)and it may have specifically evolved to induce non-coding transcripts throughout the genome depending on the presence of BORIS in a particular cell type under study. Mechanistically regulated recruitment and the subsequent release of Pol II from a DNA-bound CTCF complex indicates that the CTCF site itself could act as an attenuator and/or promoter in some locations in the genome. At imprinted genes, CTCF likely works together with BORIS (Brother of the Regulator of Imprinted States), the testis/cancer-specific CTCF-paralog that we discovered and characterized (PNAS, 2002). In addition, initiated earlier (Cell 2007) genomewide mapping of CTCF targets by ChIP-Seq with our 9 CTCF Mabs lead to understanding fundamental role of CTCF in spatiotemporal coordination of major cellular functions (Nature, 2011; 2012). By virtue of having so many vital functions CTCF became an essential gene in vertebrates, as CTCF KO mice are non-viable, and early lethality occurs at the very early embryonic stages (PloS One 2012). With respect to human disease, CTCF is a candidate tumor suppressor gene (TSG); several functional point mutations in the 11ZF DBD of CTCF have been characterized in primary cancers, in combination with the LOH of the CTCF locus. In the past year, we studied several genes and their associated regulatory sequences in an effort to elucidate the contributions of CTCF and CTCF binding sites to the regulation of gene expression. These studies included genes important for immune responses, mono-allelic multigene families of sensory receptors, as well as genes with a potential for a breakthrough in the development of new approaches for cancer treatment. Unlike somatic cells, testicular germ cells undergo meiosis rather that mitosis, - whereby CTCF is normally likely to work together with BORIS. Our recent results have identified BORIS as an anti-silencing component of undifferentiated ES and cancer cells that directly interacts with CTCF. We found earlier that functionally important dimerization between two different CTCF/DNA complexes is based on the capability of CTCF to interact with itself that requires Zn-fingers (MCB, 2004), and showed that literally same fingers are uniquely duplicated and preserved in evolution of mouse and human BORIS proteins (PNAS, 2002). Since formation of homodimeric CTCF/CTCF complexes on DNA underlie site-specific long-range interactions that serve for chromatin linking-folding in normal somatic cells (which do not express BORIS), we expect that formation of heterodimeric CTCF/BORIS complexes observed in chromatin of germ/stem and in cancer cells is likely to have many important structure-functional implications for understanding functional consequences of abnormal CTCF/BORIS dimerization, including an altered chromatin packaging mode normally driven by CTCF alone. While CTCF is mostly known as a regulator of gene expression, our data point to its potential functions in nuclear and nucleolar compartmentalization and heterochromatinization, as well as in in formation of centrosomes. We have also characterized an unusual form of CTCF protein in condensed mitotic chromosomes pointing to its roles in mitosis and meiosis, and thereby suggesting a significant housekeeping role of CTCF in spatiotemporal coordination of genome organization and chromosome segregation in dividing diploid and haploid cells. CTCF was previously shown to undergo a variety of post-translational modifications and we expanded these studies to characterize novel modifications. Another pathological aspect of the misregulated CTCF occupancy on promoter target sites is aberrant alteration of DNA methylation pattern at CTCF sites that can loose protection by DNA-bound CTCF in cancer. Both of these novel biological roles of CTCF are subjects of ongoing studies in the MPS. We also have obtained direct in vivo evidence that at least one role of BORIS is to facilitate DNA re-methylation and Pol 2 recruitment at certain intergenic CTS-sequences found in intrones and promoters of two cancer/testis genes as we published recently.
1999 年 10 月为 CTCF 颁发的第一项美国专利包括编码异常保守基因的全长 cDNA 序列,该基因在多种进化趋异物种的体细胞中普遍表达,包括果蝇、鸟类、小鼠和人类。 CTCF 是一种独特的多功能核因子,具有多种序列特异性,可控制全局基因组结构和等位基因特异性表观遗传调控的许多方面,包括直接抑制和/或激活转录、暂停相关剪接、复制计时、长程增强子-启动子通讯和激素诱导的沉默。 我们最初(MCB 2004)在体外证明了不同 CTCF/DNA 复合物之间的二聚化,最近表明通过不同类别的调控元件之间的相互作用,在体内介导通用位点特异性基因间、染色体内和染色体间连接环。 CTCF 目标位点 (CTSes) 的不同 DNA 序列。我们发现序列特异性 DNA 结合 CTCF 复合物能够在体外二聚化,这可以在体内桥接跨核染色质的不同 CTCF 结合位点。接下来,我们首先证明,在与不同的 DNA 位点结合后,CTCF 可以通过两种主要机制发挥作用:直接调节 CTS 下游的基因,或通过形成 CTCF/DNA 二聚化稳定的染色质环来间接调节。 影响相同或不同染色体上的启动子、增强子和/或印记控制区 (ICR) 之间的等位基因特异性关系。 DNA 结合 CTCF 的二聚化可能是其作为多功能染色质桥接剂和染色质环剂活性的核心,是其基本生物学功能的基础。 CTCF 的环形成活性可以自然扩展,包括形成局部体细胞染色体间配对位点,这些位点可能通过等位基因特异性转录工厂、DNA 复制工厂、5-mC/5-hmC 切除获得表观遗传共调节的潜力和 DNA 修复焦点。许多其他染色质锚定功能,例如印记标记的建立及其读取、X 染色体失活和细胞凋亡,也受到 CTCF 的调节。 CTCF 已成为间期染色质 3D 组织的关键促进者,以及细胞增殖控制的主要参与者。在某些情况下,发现 CTCF 的环形成活性伴随着/补充了对特定基因的更直接的调节。这种混合模式调节可能是天然基因调节框架的最合适的代表。 除了 CTCF 的磷酸化和聚 (ADP) 核酰化之外,我们还鉴定了 CTCF 相互作用的伴侣蛋白 Sin3A 和 YB-1,最近在对 MPS 生成的 NGS 数据进行持续解释的过程中,它们受到了越来越多的关注(与B. Ren 博士)关于全基因组 CTCF 和 CTCFL 占用、Pol 2 起始、转录暂停与剪接以及 CTCFL 阳性癌症的调控元件重新布线具有可变长度串联重复序列 (VNTR) 的移动逆转录转座子对细胞的影响通常受到 CTCF 位点特异性 SNP 增益的影响。此外,我们扩展了之前对重要 CTCF 活性的研究,这些活性直接将 CTCF 与转录机制联系起来:CTCF 与 Pol II 的结合。这种新颖的途径对影响关键 CTCF 氨基酸翻译后修饰的外部信号敏感,并提供了一种在启动子确定的 +1 位点(内含子/外显子序列)下游打开环独立转录起始位点的机制,并且它可能已经专门进化为在整个基因组中诱导非编码转录本,具体取决于所研究的特定细胞类型中 BORIS 的存在。 Pol II 从 DNA 结合的 CTCF 复合物中的机械调节募集和随后的释放表明 CTCF 位点本身可以​​在基因组中的某些位置充当衰减子和/或启动子。在印记基因方面,CTCF 可能与 BORIS(印记状态调节器的兄弟)一起工作,BORIS 是我们发现并表征的睾丸/癌症特异性 CTCF 旁系同源物(PNAS,2002)。此外,早期(Cell 2007)利用我们的 9 个 CTCF Mab 通过 ChIP-Seq 对 CTCF 靶标进行全基因组定位,有助于了解 CTCF 在主要细胞功能时空协调中的基本作用(Nature,2011;2012)。 由于具有如此多的重要功能,CTCF 成为脊椎动物中的一个必需基因,因为 CTCF KO 小鼠无法存活,并且早期致死发生在非常早期的胚胎阶段 (PloS One 2012)。 就人类疾病而言,CTCF是候选抑癌基因(TSG); CTCF 的 11ZF DBD 中的几个功能性点突变与 CTCF 基因座的 LOH 相结合,已在原发性癌症中得到了表征。在过去的一年里,我们研究了几个基因及其相关的调控序列,试图阐明 CTCF 和 CTCF 结合位点对基因表达调控的贡献。这些研究包括对免疫反应重要的基因、感觉受体的单等位基因多基因家族,以及在开发癌症治疗新方法方面具有突破潜力的基因。 与体细胞不同,睾丸生殖细胞经历减数分裂而不是有丝分裂,因此 CTCF 通常可能与 BORIS 一起发挥作用。我们最近的结果已确定 BORIS 是未分化 ES 和癌细胞的抗沉默成分,可直接与 CTCF 相互作用。 我们之前发现,两个不同 CTCF/DNA 复合物之间具有重要功能的二聚化是基于 CTCF 与自身相互作用的能力,这需要 Zn 指(MCB,2004),并且表明,实际上相同的指在进化过程中是唯一复制和保留的。小鼠和人类 BORIS 蛋白(PNAS,2002)。 由于 DNA 上同二聚 CTCF/CTCF 复合物的形成是位点特异性长程相互作用的基础,该相互作用用于正常体细胞(不表达 BORIS)中的染色质连接折叠,因此我们预计在染色质中观察到异二聚 CTCF/BORIS 复合物的形成生殖/干细胞和癌细胞中的这种结构可能对理解异常 CTCF/BORIS 二聚化的功能后果具有许多重要的结构功能影响,包括通常由 CTCF 驱动的染色质包装模式的改变 独自的。虽然 CTCF 主要被认为是基因表达的调节因子,但我们的数据指出了它在核和核仁区室化和异染色质化以及中心体形成中的潜在功能。我们还表征了浓缩有丝分裂染色体中 CTCF 蛋白的一种不寻常形式,指出了它在有丝分裂和减数分裂中的作用,从而表明 CTCF 在分裂二倍体和单倍体细胞中基因组组织和染色体分离的时空协调中具有重要的看家作用。 CTCF 之前被证明会经历各种翻译后修饰,我们扩展了这些研究以表征新的修饰。启动子靶位点 CTCF 占据失调的另一个病理学方面是 CTCF 位点 DNA 甲基化模式的异常改变,这可能会失去癌症中 DNA 结合 CTCF 的保护。 CTCF 的这两种新的生物学作用都是 MPS 正在进行的研究主题。我们还获得了直接的体内证据,表明 BORIS 的至少一个作用是促进 DNA 重新甲基化和 Pol 2 在两个癌症/睾丸基因的内含子和启动子中发现的某些基因间 CTS 序列处的招募,正如我们最近发表的。

项目成果

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Victor Lobanenkov其他文献

Victor Lobanenkov的其他文献

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{{ truncateString('Victor Lobanenkov', 18)}}的其他基金

Regulation of CTCF Functions and Target Sites by Cancer/Testis-specific CTCF Like BORIS Factor
癌症/睾丸特异性 CTCF 样 BORIS 因子对 CTCF 功能和靶位点的调节
  • 批准号:
    10272128
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Regulation of CTCF Functions and Target Sites by Cancer/Testis-specific CTCF Like BORIS Factor
癌症/睾丸特异性 CTCF 样 BORIS 因子对 CTCF 功能和靶位点的调节
  • 批准号:
    10692106
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Deciphering CTCF code in mammalian host and viral epigenomes
破译哺乳动物宿主和病毒表观基因组中的 CTCF 代码
  • 批准号:
    10927769
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Regulation of CTCF Functions and Target Sites by Cancer/Testis-specific CTCF Like BORIS Factor
癌症/睾丸特异性 CTCF 样 BORIS 因子对 CTCF 功能和靶位点的调节
  • 批准号:
    10927815
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
  • 批准号:
    8336243
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
  • 批准号:
    8946422
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
  • 批准号:
    9354824
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Normal and Pathologic Functions of CTCF and Its Distinct Classes of DNA-targets
CTCF 的正常和病理功能及其不同类型的 DNA 靶标
  • 批准号:
    8336142
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Normal and Pathologic Functions of CTCF and Its Distinct Classes of DNA-targets
CTCF 的正常和病理功能及其不同类型的 DNA 靶标
  • 批准号:
    7964430
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:
Epigenetic Regulation of Normal and Pathologic CTCF Functions by BORIS
BORIS 对正常和病理 CTCF 功能的表观遗传调控
  • 批准号:
    7964638
  • 财政年份:
  • 资助金额:
    $ 76.58万
  • 项目类别:

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