Deregulation of epigenetic marks is correlated to differential exon usage of developmental genes

ABSTRACTAlternative exon usage is known to affect a large portion of genes in mammalian genomes. Importantly, different splice forms sometimes lead to distinctly different protein functions. We analyzed data from the Human Epigenome Atlas (version 9) whereby we connected the differential usage of exons in various developmental stages of human cells/tissues to differential epigenetic modifications at the exon level. In total, we analyzed 19 human tissues, adult cells, and cultured cells that mimic early developmental stages. We found that the differential occurrence of protein isoforms across developmental stages was often associated with changes in histone marks at exon boundary regions. Many of the genes that are differentially regulated at the exon level were found to be functionally associated with development and metabolism.

DNA-Encoded Chromatin Structural Intron Boundary Signals Identify Conserved Genes with Common Function

The regulation of metazoan gene expression occurs in part by pre-mRNA splicing into mature RNAs. Signals affecting the efficiency and specificity with which introns are removed have not been completely elucidated. Splicing likely occurs cotranscriptionally, with chromatin structure playing a key regulatory role. We calculated DNA encoded nucleosome occupancy likelihood (NOL) scores at the boundaries between introns and exons across five metazoan species. We found that (i) NOL scores reveal a sequence-based feature at the introns on both sides of the intron-exon boundary; (ii) this feature is not part of any recognizable consensus sequence; (iii) this feature is conserved throughout metazoa; (iv) this feature is enriched in genes sharing similar functions: ATPase activity, ATP binding, helicase activity, and motor activity; (v) genes with these functions exhibit different genomic characteristics; (vi)in vivonucleosome positioning data confirm ontological enrichment at this feature; and (vii) genes with this feature exhibit unique dinucleotide distributions at the intron-exon boundary. The NOL scores point toward a physical property of DNA that may play a role in the mechanism of pre-mRNA splicing. These results provide a foundation for identification of a new set of regulatory DNA elements involved in splicing regulation.

Analysis of Pneumocystis cariniiIntrons

ABSTRACT Pneumocystis carinii is an ascomycete phylogenetically related to Schizosaccharomyces pombe. Little is known about gene regulation in P. carinii. The removal of introns from pre-mRNA requires spliceosomal recognition of the intron-exon boundary. In S. pombe and higher eukaryotes, this boundary and a branch site within the intron are conserved. We recently demonstrated that P. carinii cdc2 cDNA can complement S. pombe containing conditional mutations of cdc2, an essential gene involved in cell cycle regulation. We next tested whether P. carinii genomic cdc2 (with six introns) could also complement S. pombe cdc2 mutants and found genomic sequences incapable of this activity. Reverse transcriptase PCR confirmed the inability of the S. pombe cdc2 mutants to splice the P. carinii genomiccdc2. Analysis of 83 introns from 19 P. cariniiprotein-encoding genes demonstrated that the sequence GTWWDW functions as a donor consensus in P. carinii, whereas YAG serves as an acceptor consensus. These sequences are similar in S. pombe; however, a branch site sequence was not found in theP. carinii genes studied.