Abstract:Previous studies have shown that Mixed Lineage Leukemia 1 (MLL1 or MLL) binds a group of CpG-rich motifs known as morphemes. To examine whether occurrences of MLL1 morphemes in genomic DNA may influence codon utilization, we analyzed the frequency of various 9-mers in human cDNAs and in total human genomic DNA. We uncovered preferential utilization of GGC for Gly, GCG for Ala, CCG for Pro, and TCG for Ser, in coding sequences (CDSs) that included MLL1 morphemes. We also examined weighted occurrences of CDS 9-m… Show more
“…The MLL1 morphemes contain 2–3 CpGs and occur in both the forward and the reverse orientation in genomic DNA ( Table 1 ). Even though the MLL1 morphemes are dispersed along the chromosomal DNA, often they are clustered in CGIs [3] , [6] . Examples include two CGIs (CpG36 and CpG72) associated with the Plagl1 / Zac1 loci ( Fig.…”
Section: Datamentioning
confidence: 99%
“…As a consequence of length-variability of CGIs [7] , morpheme-frequencies in the islands vary: for examples, see Refs. [3] , [6] . Fig.…”
Section: Datamentioning
confidence: 99%
“…Clustering of the MLL1 morphemes in CGIs is more apparent in shorter DNA segments; for examples see Refs. [3] , [6] . …”
While MLL1 activates gene expression in most tissues, ZFP57 represses transcription. MLL1 selectively interacts with a group of nonmethylated DNA sequences known as the MLL1 morphemes. ZFP57 associates with a methylated hexamer (ZFBS), dispersed in the genomic DNA segments known as Imprinted Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs), to maintain allele-specific gene repression. We have identified a set of composite DNA elements (ZFBS-Morph overlaps) that provides the sequence context of ZFBS in the canonical ICRs/gDMRs. This report provides tables listing the nucleotide sequences of the MLL1 morphemes and ZFBS-Morph overlaps. The report also offers links to the data repository at Purdue University, for downloading the positions of the MLL1 morphemes, the ZFP57 binding site, and the ZFBS-Morph overlaps in the mouse genome.
“…The MLL1 morphemes contain 2–3 CpGs and occur in both the forward and the reverse orientation in genomic DNA ( Table 1 ). Even though the MLL1 morphemes are dispersed along the chromosomal DNA, often they are clustered in CGIs [3] , [6] . Examples include two CGIs (CpG36 and CpG72) associated with the Plagl1 / Zac1 loci ( Fig.…”
Section: Datamentioning
confidence: 99%
“…As a consequence of length-variability of CGIs [7] , morpheme-frequencies in the islands vary: for examples, see Refs. [3] , [6] . Fig.…”
Section: Datamentioning
confidence: 99%
“…Clustering of the MLL1 morphemes in CGIs is more apparent in shorter DNA segments; for examples see Refs. [3] , [6] . …”
While MLL1 activates gene expression in most tissues, ZFP57 represses transcription. MLL1 selectively interacts with a group of nonmethylated DNA sequences known as the MLL1 morphemes. ZFP57 associates with a methylated hexamer (ZFBS), dispersed in the genomic DNA segments known as Imprinted Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs), to maintain allele-specific gene repression. We have identified a set of composite DNA elements (ZFBS-Morph overlaps) that provides the sequence context of ZFBS in the canonical ICRs/gDMRs. This report provides tables listing the nucleotide sequences of the MLL1 morphemes and ZFBS-Morph overlaps. The report also offers links to the data repository at Purdue University, for downloading the positions of the MLL1 morphemes, the ZFP57 binding site, and the ZFBS-Morph overlaps in the mouse genome.
“…Promoter-associated islands often extend into the transcribed sequences, even into protein-coding exons [14]. The occurrences of the MLL1 morphemes in these exons impact codon utilization and preservation [15], perhaps reflecting the importance of these CpG-rich motifs in genome-associated functions.…”
In mammals, parent-of-origin-specific gene expression is regulated by specific genomic DNA segments known as Imprinting Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs). In the mouse genome, the known ICRs/gDMRs often include clusters of a set of composite-DNA-elements known as ZFBS-morph overlaps. These elements consist of the ZFP57 binding site (ZFBS) overlapping a subset of the MLL1 morphemes. To improve detection of such clusters, we created density-plots. In genome-wide analyses, peaks in these plots pinpointed ~90% of the known ICRs/gDMRs and located candidate ICRs within relatively long genomic DNA sections. In several cases, the candidate ICRs mapped to chromatin boundaries, to a subset of gene-transcripts, or to both. By viewing the plots at the UCSC genome browser, we could examine the candidate ICRs in the context of the genes in their vicinity. This strategy uncovered several potential imprinted genes with a broad range of physiologically important functions. Examples include: folliculogenesis; lineage commitment of murine embryonic stem cells; the development of the junctional zone of the placenta; left-right patterning of the body axis; the development of the neocortex, hippocampus, and cerebellum; postnatal vision; self-renewal of mouse spermatogonial stem cells; and histone-to-protamine replacement during spermatogenesis.
Predicted imprinted genes: Arid1b,
“…Since these units are CpG-rich, they are spread across the CpG islands. In the islands that encompass coding exons, the morphemes impact codon utilization [ 28 ]. Overall, in the human genome, CpG-rich promoters encompass many CpG-rich motifs with potential regulatory characteristics [ 29 , 30 ].…”
Background
In mammals, Imprinting Control Regions (ICRs) regulate a subset of genes in a parent-of-origin-specific manner. In both human and mouse, previous studies identified a set of CpG-rich motifs occurring as clusters in ICRs and germline Differentially Methylated Regions (gDMRs). These motifs consist of the ZFP57 binding site (ZFBS) overlapping a subset of MLL binding units known as MLL morphemes. MLL or MLL1 (Mixed Lineage Leukemia 1) is a relatively large multidomain protein that plays a central role in the regulation of transcription. The structures of both MLL1 and MLL2 include a domain (MT) that binds CpG-rich DNA and a conserved domain (SET) that methylates lysine 4 in histone H3 producing H3K4me3 marks in chromatin.
Results
Since genomic imprinting impacts many developmental and key physiological processes, we followed a previous bioinformatics strategy to pinpoint ICR positions in the Bos taurus genome. Initial genome-wide analyses involved finding the positions of ZFP57 binding sites, and the CpG-rich motifs (ZFBS-morph overlaps) along cattle chromosomal DNA. By creating plots displaying the density of ZFBS-morph overlaps, we removed background noise and thus improved signal detection. With the density-plots, we could view the positions of peaks locating known and candidate ICRs in cattle DNA. Our evaluations revealed the correspondence of peaks in plots to reported known and inferred ICRs/DMRs in cattle. Beside peaks pinpointing such ICRs, the density-plots also revealed additional peaks. Since evaluations validated the robustness of our approach, we inferred that the additional peaks may correspond to candidate ICRs for imprinted gene expression.
Conclusion
Our bioinformatics strategy offers the first genome-wide approach for systematically localizing candidate ICRs. Furthermore, we have tailored our datasets for upload onto the UCSC genome browser so that researchers could find known and candidate ICRs with respect to a wide variety of annotations at all scales: from the positions of Single Nucleotide Polymorphisms (SNPs), to positions of genes, transcripts, and repeated DNA elements. Furthermore, the UCSC genome browser offers tools to produce enlarged views: to uncover the genes in the vicinity of candidate ICRs and thus discover potential imprinted genes for experimental validations.
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