Role Of Boris/ctcf-pairing In Development, Gene-imprinti

Boris/ctcf 配对在发育、基因印记中的作用

• 批准号: 6809087
• 负责人: VICTOR LOBANENKOV
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6809087
• 关键词: DNA methylation; Wilms' tumor; breast neoplasms; gene induction /repression; gene mutation; genetic promoter element; genetically modified animals; genomic imprinting; microarray technology; neoplasm /cancer genetics; nucleic acid sequence; prostate neoplasms; protein structure function; protooncogene; site directed mutagenesis; tissue /cell culture; transcription factor; tumor suppressor genes; tumor suppressor proteins

Novel cellular oncogenes and tumor suppressor genes (TSG), which would fit the classic criteria of a cancer gene associated with already recognized chromosome hot spots (such as the loci of recurrent gains at 20q13 and of LOH at 16q22), remain elusive. Therefore, most recent advances in cancer research include re-thinking of the genetic two-hits model to emphasize epigenetic mechanisms - aberrant methylation of regulatory regions, loss of imprinting (LOI) at IGF2/H19 and other loci, and/or heterogeneity in epigenetic reprogramming/maintenance. The most recent results obtained in the Molecular Pathology Section suggest that each of these seemingly unrelated cancer events, plus one of the other most frequently observed features of cancer - deregulated expression of MYC, - might be causally linked to the unique pair of paralogous genes mapped on chromosomes 16q22 and 20q13. Both genes have been discovered by scientists lead by the Head of MPS LIP NIAID, Dr. Victor Lobanenkov, and both were patented for a wide range of applications in basic and clinical medicine. One gene was named CTCF (for CCTC-binding factor), and the other BORIS (for Brother of the Regulator of Imprinted Sites, referring to the role of CTCF in reading of gene imprinting marks). Two siblings are equipped with the identical 11 Zn-finger (ZF) domain to interact with the same spectrum of CTCF/BORIS-binding sites, but diverge at the amino- and carboxy-termini. Normally, only CTCF but not BORIS is expressed in all somatic cells. During male germ cell differentiation, the pair displays mutually exclusive expression pattern that correlates with the patterns for (1) genome-wide re-establishing of DNA-methylation marks and (2) certain testis-specific chromatin-remodeling factors, and DNMTs. While CTCF has properties of a candidate TSG at 16q22, abnormally activated BORIS is oncogenic, and found to be expressed in many malignancies with gains or amplifications at 20q13. Novel data obtained by MPS and collaborators with several types of such cancers lead to following major conclusions: (i) BORIS is a new member of the so-called cancer/testis (CT) gene family with a great promise for cancer diagnostic and therapy applications; and (ii) the most common mechanism to deregulate TSG function of CTCF on one chromosome may result from the abnormal activation of BORIS on another. Both published and ongoing studies illustrate contributions of CTCF/BORIS-pair in epigenetic gene regulation and cell proliferation control by describing in details the two sets of distinct CTCF-binding sites characterized in IGF2/H19 and in MYC loci. These studies show that -combinatorial mode- and -in vivo accessibility- to be the main key words to understanding of functional consequences resulting from in vivo interactions of CTCF and BORIS with unusually diverged and long target DNA sequences. The main papers, published on CTCF and BORIS genes by September 2002, include, but not limited to: -Klenova et.al., The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer.? Seminars in Cancer Biol. 2002 Oct 12(5): 399-414; -Loukinov et.al., BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci U S A. 2002 May 14; 99(10): 6806-6811; -Kanduri et.al., Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region. Mol Cell Biol. 2002 May 22(10): 3339-3344; -Filippova et.al. Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity. Cancer Res. 2002 Jan 1; 62(1): 48-52.

新的细胞癌基因和肿瘤抑制基因（TSG），将符合与已经识别的染色体热点相关的癌症基因的经典标准（如20q13的复发性获益位点和16q22的LOH位点），仍然难以捉摸。因此，癌症研究的最新进展包括重新思考遗传双击模型，以强调表观遗传机制-调控区域的异常甲基化，IGF2/H19和其他位点的印迹丢失（LOI），和/或表观遗传重编程/维持的异质性。分子病理学部分获得的最新结果表明，这些看似无关的癌症事件，加上癌症的另一个最常观察到的特征- MYC的表达失调，可能与染色体16q22和20q13上的独特的同源基因对有因果关系。这两种基因都是由MPS LIP NIAID负责人Victor Lobanenkov博士领导的科学家发现的，并且都获得了基础和临床医学广泛应用的专利。其中一个基因命名为CTCF （cctc结合因子），另一个命名为BORIS （Brother of the Regulator of imprinting Sites，指CTCF在基因印迹标记读取中的作用）。两个兄弟姐妹具有相同的11 Zn-finger （ZF）结构域，与CTCF/ boris结合位点的相同光谱相互作用，但在氨基端和羧基端存在分歧。正常情况下，所有体细胞只表达CTCF，不表达BORIS。在男性生殖细胞分化过程中，这对基因表现出互斥的表达模式，这种表达模式与(1)dna甲基化标记的全基因组重建和(2)某些睾丸特异性染色质重塑因子和dnmt的模式相关。虽然CTCF在16q22位点具有候选TSG的特性，但异常激活的BORIS具有致癌性，并且在20q13位点获得或扩增的许多恶性肿瘤中表达。MPS及其合作者在几种类型的此类癌症中获得的新数据导致以下主要结论：(i) BORIS是所谓的癌症/睾丸（CT）基因家族的新成员，在癌症诊断和治疗应用方面具有很大的前景；（ii）一条染色体上CTCF的TSG功能失调的最常见机制可能是另一条染色体上BORIS的异常激活。已发表的和正在进行的研究都通过详细描述IGF2/H19和MYC基因座中两组不同的CTCF结合位点，说明了CTCF/ boris对表观遗传基因调控和细胞增殖控制的贡献。这些研究表明，组合模式和体内可及性是理解CTCF和BORIS与异常分化和长靶DNA序列在体内相互作用所导致的功能后果的主要关键词。截至2002年9月发表的关于CTCF和BORIS基因的主要论文包括但不限于：-Klenova et.al。新的BORIS + CTCF基因家族在正常生物学和癌症的表观遗传学中具有独特的作用。癌症生物学研讨会2002年10月12日(5):399-414；-Loukinov出版社。BORIS是一种与表观遗传重编程事件相关的新型雄性种系特异性蛋白，它与CTCF具有相同的11-锌指结构域，CTCF是一种参与读取体细胞印迹标记的绝缘体蛋白。美国国家科学基金2002年5月14日；99 (10): 6806 - 6811;-Kanduri出版社。多个核小体定位位点调控ctcf介导的H19印迹控制区绝缘子功能。中华生物医学杂志2002年5月22日（10）：3339-3344；-Filippova出版社。肿瘤相关的CTCF转录因子锌指突变选择性地改变其dna结合特异性。2002年1月1日；62(1): 52。