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A Bioinformatics Approach to Discover the Evolutionary Origin of the PTBP Splicing Regulators
Author(s) -
Pina Jeffrey,
Ontiveros Robert Jordan,
Keppetipola Niroshika,
Nikolaidis Nikolas
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.802.16
Subject(s) - biology , rna splicing , alternative splicing , exon , polypyrimidine tract binding protein , rna recognition motif , genetics , exonic splicing enhancer , gene , genome , transcriptome , computational biology , rna , gene expression
Polypyrimidine binding tract proteins (PTBPs) are members of the hnRNP family and are involved in the modulation of alternative splicing, serving as both repressors and activators of cassette exon inclusion in mature mRNA (Kafasla et al, 2012). The human genome encodes for three different PTBP paralogs, PTBP1, PTBP2 and PTPB3. These homologous proteins are highly similar in primary structure and domain organization, which is characterized by a N‐terminal domain and four RNA recognition motifs (RRMs) connected via linker regions. PTBPs share >70% sequence identity and differ in their tissue expression with PTBP1 being expressed nearly ubiquitously while PTBP2 and PTBP3 show more tissue specific expression (Keppetipola et al, 2012; Tan et al, 2015). Changes in the expression of PTBP1 and PTBP2 have been found to be critical in the process of neuronal differentiation and maturation (Li et al, 2014). PTBP1 has been observed to be overexpressed in ovarian cancer cells (He et al, 2007) and PTBP1 and PTBP2 have been implicated in the splicing of transcripts that promote proliferation of glioma (Cheung et al, 2009). Inhibition of PTBP3 expression in gastric cancer cells induced apoptosis (Liang et al, 2017). Therefore, further understanding of PTBPs may provide insight to how related proteins exert differential splicing outcomes and may provide therapeutic targets for drug design. In this study, we sought to characterize PTBP by elucidating its evolutionary history via sequence and phylogenetic analyses. Homologous sequences, including vertebrate, invertebrate, plant and fungi sequences, were identified by using BLAST search tools across various species databases. Multiple sequencing alignments (MSAs) and phylogenetic analyses were performed using different methods in MEGA6. Our current results reveal that the three human PTBP paralogs have orthologs found ubiquitously amongst jawed vertebrate species. In contrast, jawless vertebrate and invertebrate species contain only one homologous protein. This finding suggests that the gene duplication events that produced the three human PTBPs occurred within the ancestor of all jawed vertebrates. Plant species also have two or three PTBP homologs; however, these do not cluster with their animal homologs. This suggests that in both animal and plant species the genes multiplied independently. Fungi, which are unicellular organisms, contain one or no PTBP homologs. MSAs have also revealed a variety of residues within the RRMs that are highly conserved across the various PTBP orthologs surveyed, which suggests their functional and structural importance. We are conducting analysis of intron and synteny conservation as well as 3D structure comparisons to further develop the tentative conclusions posited. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .