Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies
Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies
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DOI：
10.1073/pnas.0308195101
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发表时间：
2004-05-11
影响因子：
11.1
通讯作者：
Green, AR
中科院分区：
文献类型：
--
作者：
Li, J;Bench, AJ;Green, AR
L3MBTL编码Polycomb蛋白家族的一个成员，它与Trithorax组蛋白一起负责基因活性模式的协调调节。Polycomb家族的成员还调节正常和恶性造血干细胞的自我更新。L3MBTL位于20号染色体的一个区域，该区域的缺失与髓系恶性肿瘤相关，是一个很好的20Q靶基因候选基因。然而，在20Q缺失的患者或细胞遗传学正常的患者中尚未发现L3MBTL的突变。在这里，我们证明了两个CpG岛的单等位基因甲基化与L3MBTL的转录沉默相关，并且在来自两个家庭的五个个体中，L3MBTL的转录发生在父系衍生的等位基因上。父系来源的等位基因在多种造血细胞类型以及骨髓来源的间充质细胞中都有表达。与髓系恶性肿瘤相关的20Q缺失导致未甲基化或甲基化的等位基因丢失。我们的结果表明，L3MBTL代表了一个以前未被描述的印记基因，一个脊椎动物的多梳组基因，被证明受到这种机制的调节，并可能与与20Q缺失相关的髓系恶性肿瘤的发病机制有关。
L3MBTL encodes a member of the Polycomb family of proteins, which, together with Trithorax group proteins, is responsible for the coordinated regulation of patterns of gene activity. Members of the Polycomb family also regulate self renewal of normal and malignant hematopoietic stem cells. L3MBTL lies in a region of chromosome 20, deletion of which is associated with myeloid malignancies and represents a good candidate for a 20q target gene. However, mutations of L3MBTL have not been identified in patients with 20q deletions or in cytogenetically normal patients. Here we demonstrate that monoallelic methylation of two CpG islands correlates with transcriptional silencing of L3MBTL, and that L3MBTL transcription occurs from the paternally derived allele in five individuals from two families. Expression of the paternally derived allele was observed in multiple hematopoietic cell types as well as in bone marrow derived mesenchymal cells. Deletions of 20q associated with myeloid malignancies resulted in loss of either the unmethylated or methylated allele. Our results demonstrate that L3MBTL represents a previously undescribed imprinted locus, a vertebrate Polycomb group gene shown to be regulated by this mechanism, and has implications for the pathogenesis of myeloid malignancies associated with 20q deletions.