title: Discovery of MLL1 binding units, their localization to CpG Islands, and their potential function in mitotic chromatin.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. bina@purdue.edu.
authors.forename: Minou
authors.initials: M
authors.lastname: Bina
authors.forename: Phillip
authors.initials: P
authors.lastname: Wyss
authors.forename: Elise
authors.initials: E
authors.lastname: Novorolsky
authors.forename: Noorfatin
authors.initials: N
authors.lastname: Zulkelfi
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.forename: Randi
authors.initials: R
authors.lastname: Price
authors.forename: Matthew
authors.initials: M
authors.lastname: Fay
authors.forename: Zach
authors.initials: Z
authors.lastname: Gutmann
authors.forename: Brian
authors.initials: B
authors.lastname: Fogler
authors.forename: Daidong
authors.initials: D
authors.lastname: Wang
mesh_terms: D001483:Base Sequence; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D015894:Genome, Human; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D059372:Nucleotide Motifs; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D012319:RNA Polymerase II / Q000235:genetics
chemical_list: D002843:Chromatin; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D004247:DNA; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II