Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
BMC Genomics. 2013 Dec 28;14:927. doi: 10.1186/1471-2164-14-927.
Mixed Lineage Leukemia 1 (MLL1) is a mammalian ortholog of the Drosophila Trithorax. In Drosophila, Trithorax complexes transmit the memory of active genes to daughter cells through interactions with Trithorax Response Elements (TREs). However, despite their functional importance, nothing is known about sequence features that may act as TREs in mammalian genomic DNA.
By analyzing results of reported DNA binding assays, we identified several CpG rich motifs as potential MLL1 binding units (defined as morphemes). We find that these morphemes are dispersed within a relatively large collection of human promoter sequences and appear densely packed near transcription start sites of protein-coding genes. Genome wide analyses localized frequent morpheme occurrences to CpG islands. In the human HOX loci, the morphemes are spread across CpG islands and in some cases tail into the surrounding shores and shelves of the islands. By analyzing results of chromatin immunoprecipitation assays, we found a connection between morpheme occurrences, CpG islands, and chromatin segments reported to be associated with MLL1. Furthermore, we found a correspondence of reported MLL1-driven "bookmarked" regions in chromatin to frequent occurrences of MLL1 morphemes in CpG islands.
Our results implicate the MLL1 morphemes in sequence-features that define the mammalian TREs and provide a novel function for CpG islands. Apparently, our findings offer the first evidence for existence of potential TREs in mammalian genomic DNA and the first evidence for a connection between CpG islands and gene-bookmarking by MLL1 to transmit the memory of highly active genes during mitosis. Our results further suggest a role for overlapping morphemes in producing closely packed and multiple MLL1 binding events in genomic DNA so that MLL1 molecules could interact and reside simultaneously on extended potential transcriptional maintenance elements in human chromosomes to transmit the memory of highly active genes during mitosis.
混合谱系白血病 1（MLL1）是果蝇 Trithorax 的哺乳动物直系同源物。在果蝇中，Trithorax 复合物通过与 Trithorax 反应元件（TREs）相互作用，将活跃基因的记忆传递给子细胞。然而，尽管它们具有重要的功能，但对于可能作为哺乳动物基因组 DNA 中 TRE 的序列特征却一无所知。
通过分析已报道的 DNA 结合测定结果，我们确定了几个富含 CpG 的基序作为潜在的 MLL1 结合单位（定义为语素）。我们发现这些语素分散在相对大量的人类启动子序列中，并且在蛋白质编码基因的转录起始位点附近密集包装。全基因组分析将频繁出现的语素定位到 CpG 岛。在人类 HOX 基因座中，语素散布在 CpG 岛之间，在某些情况下，延伸到岛屿的周围岸区和架区。通过分析染色质免疫沉淀测定的结果，我们发现语素的出现、CpG 岛和与 MLL1 相关的染色质片段之间存在联系。此外，我们发现报告的 MLL1 驱动的“标记”区域与 CpG 岛中频繁出现的 MLL1 语素之间存在对应关系。
我们的结果表明 MLL1 语素参与了定义哺乳动物 TRE 的序列特征，并为 CpG 岛提供了新的功能。显然，我们的研究结果为哺乳动物基因组 DNA 中潜在 TRE 的存在以及 CpG 岛与 MLL1 介导的基因标记之间的联系提供了第一个证据，以在有丝分裂过程中传递高度活跃基因的记忆。我们的研究结果进一步表明，重叠语素在产生紧密包装和多个 MLL1 在基因组 DNA 中的结合事件中发挥作用，以便 MLL1 分子可以相互作用并同时存在于人类染色体上扩展的潜在转录维持元件上，以在有丝分裂过程中传递高度活跃基因的记忆。
