BWS and Embryonal Tumor Suppressor Genes on 11p15

超出空间 提供了 Beckwith-Wiedemann综合征（BWS）是由癌症引起的癌症易感性疾病的范例， 表观遗传机制，它作为一个模型，癌症表观遗传学的一般理解。患者 患有BWS的儿童患肾母细胞瘤（WT）和其他儿童胚胎癌的风险增加800倍， 以及出生缺陷，包括尺寸增大、器官过度生长和中线闭合缺陷。我们之前 将BWS定位于11 p15区域，该区域含有在WT和普通成人中丢失的未鉴定的WT基因（WT 2 癌的在这个MERIT奖的前31/2年里，我们已经完成了第一个表观基因型-表型 任何疾病的研究，表明BWS是一种与基因H19和IGF 2相邻的基因综合征 LIT 1和p57^p2导致出生缺陷。我们第一次将任何疾病与 辅助生殖技术（ART），显示与BWS中LIT 1的表观遗传变化相关。 我们还鉴定了BWS中的第一个染色体微缺失， T^pz和其他基因，以及LIT 1中的一个新的染色质绝缘子。最后，我们确定了几个潜在的 关键的新基因，包括定位于线粒体的沉默信息调节因子（SIRT 3）， 候选WT 2基因。这种以前不被重视的印记基因编码一种蛋白质，定位于 在WT中，其表达丢失，杂合性丢失或印记丢失，并且其抑制了细胞核的表达。 WT和其他肿瘤的生长。 在MERIT扩展中，我们将确定家族性BWS中的其他微缺失和调控基因。 其中的元素和基因。我们将研究ART诱导的表观遗传缺陷的机制， BWS通过体外培养和受精小鼠配子，和表观遗传缺陷的影响， 癌症在后代中的发病率。我们将研究30%的BWS患者的分子基础， 甲基化变化，以及特发性偏侧肥大患者，使用新的染色质免疫沉淀- 在本赠款期间开发的方法。我们将研究基因型与 和表观基因型。我们将继续确定新的基因和调控元件在BWS，使用 表观基因组和功能方法，包括p57 KIP 2的推定增强子和低血糖的基因， 米娅我们将对候选WT 2基因和另一个基因identi进行遗传和功能分析。 在当前的授权期内，可以介导LIT 1功能。这些研究将包括体内小鼠 模型，核仁蛋白结合的生物化学研究，以及结合伴侣的鉴定，包括 新的绝缘子蛋白结合LIT 1。这项工作应继续提供开拓性的见解， 癌症的遗传学和表观遗传学，以及环境和发育失误在 表观遗传破坏，对理解人类癌症的机制具有广泛的意义。

EXCEED THE SPACE PROVIDED. Beckwith-Wiedemann Syndrome (BWS) is the paradigm of cancer-predisposing disorders caused by an epigenetic mechanism, and it serves as a model for a general understanding of cancer epigenetics. Patients with BWS have an 800-fold increased risk of Wilms tumor (WT) and other embryonal cancers of childhood, as well as birth defects including increased size, organ overgrowth, and midline closure defects. We earlier mapped BWS to a region of 11 p15 containing an unidentified WT gene (WT2) lost in WT and common adult cancers. In the first 31/2 years of this MERIT award, we have performed the first epigenotype-phenotype study of any disorder, showing that BWS is a contiguous gene syndrome with the genes H19 and IGF2 causing cancer, and LIT1 and p57^p2 causing birth defects. We made the first link between any disorder and assisted reproductive technology (ART), showing an association with epigenetic changes in LIT1 in BWS. We also identified the first chromosomal microdeletion in BWS, identifying an imprinting element controlling T^pz and other genes, and a novel chromatin insulator in LIT1. Finally, we identified several potentially critical novel genes, including a silence information regulator (SIRT3) localized to mitochondria, and a candidate WT2 gene. This previously unappreciated imprinted gene encodes a protein localized to the nucleolus, its expression is lost in WT with loss of heterozygosity or loss of imprinting, and it suppresses the growth of WT and other tumors. In the MERIT extension, we will identify additional microdeletions in familial BWS and the regulatory elements and genes within them. We will investigate the mechanism of ART-induced epigenetic defects in BWS through in vitro culture and fertilization of mouse gametes, and the effect of epigenetic defects on cancer incidence in the offspring. We will investigate the molecular basis of the 30% of BWS patients without methylation changes, as well as idiopathic hemihypertrophy patients, using new chromatin immunoprecipita- tion approaches developed in the current grant period. We will investigate the relationship between genotype and epigenotype in families. We will continue to identify new genes and regulatory elements in BWS, using epigenomic and functional approaches, including a putative enhancer for p57KIP2 and a gene for hypoglyce- mia. We will perform genetic and functional analyses of the candidate WT2 gene and another gene, identi- fied in the current grant period, that may mediate LIT1 function. These studies will include in vivo mouse models, biochemical studies of nucleolar protein binding, and identification of binding partners, including a novel insulator protein that binds to LIT1. This work should continue to provide pioneering insights into the genetics and epigenetics of cancer, as well as the role of environmental and developmental miscues in epigenetic disruption, with broad implications for understanding the mechanism of human cancer.