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. 2022 Jul 27;54(1):54.
doi: 10.1186/s12711-022-00745-3.

Origin, evolution, and tissue-specific functions of the porcine repetitive element 1

Min Zheng  1 , Tianfu Guo  2 , Bin Yang  2 , Zhiyan Zhang  3 , Lusheng Huang  4
Affiliations

Origin, evolution, and tissue-specific functions of the porcine repetitive element 1

Min Zheng et al. Genet Sel Evol. .

Abstract

Background: The porcine repetitive element 1 (PRE1) is the most abundant short interspersed nuclear element (SINE) in the Sus scrofa genome and it has been suggested that some PRE1 can have regulatory functions. The million copies of PRE1 in the porcine genome have accumulated abundant CpG dinucleotides and unique structural variations, such as direct repeats and patterns of sequence degeneration. The aims of this study were to analyse these structural variations to trace the origin and evolutionary pattern of PRE1 and to investigate potential methylation-related functions of PRE1 based on methylation patterns of PRE1 CpG dinucleotides in different tissues.

Results: We investigated the evolutionary trajectory of PRE1 and found that PRE1 originated from the ancestral CHRS-S1 family through three main successive partial duplications. We found that the partial duplications and deletions of PRE1 were likely due to RNA splicing events during retrotransposition. Functionally, correlation analysis showed that the methylation levels of 103 and 261 proximal PRE1 were, respectively, negatively and positively correlated with the expression levels of neighboring genes (Spearman correlation, P < 0.01). Further epigenomic analysis revealed that, in the testis, demethylation of proximal PRE1 in the HORMAD1 and HACD3 genes had tissue-specific enhancer and promoter functions, while in the muscle, methylation of proximal PRE1 repeats in the TCEA3 gene had an enhancer function.

Conclusions: The characteristic sequences of PRE1 reflect unique patterns of origin and evolution and provide a structural basis for diverse regulatory functions.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Characterization of PRE1. a Length distribution of whole PRE1, head–body, and tail. b Nucleotide content of the head–body, tail, and target site duplications (TSD). c GC content of the head–body, tail, and target site duplications (TSD). Different letters above the bars indicate a significant difference (P < 0.01). d, e Distribution of the CG content and OE values in the head–body
Fig. 2
Fig. 2
Structure of PRE1. a Origin, evolution, and structure of PRE1. The green shadows show the highly conserved A box and B box within the bipartite RNA polymerase III promoter elements. The colored arrows show the observed direct repeats in different PRE1 lineages. The colored boxes on the sequences show the proposed duplication sequences. b X-type secondary structure of PRE1 RNA. The sequences of the A, B, and C arms are marked in panel (a). The colored B and C arms show the secondary structures of the F direct repeat and R direct repeat, respectively
Fig. 3
Fig. 3
The splicing model of PRE1. a Neighbour-joining tree based on consensus sequences of 15 PRE1 lineages, several affected PRE1, and consensus sequences of CRHS from Sus scrofa, Bos taurus and Capra hircus. The PRE1 shown in black font belong to class I, and those in red belong to class II. b Principal component analysis based on the Needleman–Wunsch genetic distance from PRE1 to the consensus sequences of 15 PRE1 lineages. Red and black dot sets represent class I and class II PRE1, respectively. The small image at the bottom left shows the specular mapping (x = 1) of class I PRE1. c IGV window of the promoter region of the TECA3 gene. The green box shows the PRE1 region in Sus scrofa. The six resequencing reads data downloaded from public databases, Sus barbatus (ERR173177) [16], Sus cebifrons (ERR173209) [16], Sus celebensis (ERR173210) [16], Sus verrucosus (ERR173211) [16], Phacochoerus africanus (ERR173203) [16], Sus scrofa (11-146,206) [36]. d Number of PRE1 that overlap with known exons. e Splicing signals are enriched in direct repeats. The x axis represents the base position on the consensus sequence. The font colour indicates the type of splicing signal, the physical locations of the splicing signals, and the transcript names. Numbers 3 and 5 represent the 3′ splicing signal and 5′ splicing signal in PRE1, respectively, and T represents the 3′ splicing signal in the reverse complementary sequence of PRE1. f Splicing model for the PRE1 body and degenerate sequences
Fig. 4
Fig. 4
Duplication and deletion mechanisms in the splicing model. a PCA based on the genetic distances among different direct repeats from the class I PRE1, class II PRE1, and PRE1k lineage. We extracted the sequences in PRE1k and class II PRE1 that were homologous to the two direct repeats in class I PRE1, and we used the genetic distance matrix among these homologous sequences for PCA. The PRE1k represented the homologous cluster before the direct repeats were formed, and the class II PRE1 represented the homologous cluster after removal of a 46-bp sequence from the ancestral class I PRE1 by splicing. b Splicing model of tandem PRE1 for partial duplications and deletions. The top panel shows the three basic models for the formation of three different combined PRE1 types. The bottom panel shows that two tandem quasi-dimeric PRE1 form a combined quasi-oligomeric PRE1 or a combined PRE1 with degenerate direct repeats. c Genetic distance of the three direct repeats (repeat A, repeat B, and repeat C) from 82 quasi-oligomeric PRE1 based on principal component analysis (PCA). The genetic distance matrix among the three direct repeats was used for PCA. Repeat B cluster was between the repeat A and C clusters that supported the splicing model for the formation of quasi-oligomeric PRE1. Solid geometric symbols highlight five quasi-oligomeric PRE1 that are the most similar A repeats. d Genetic distances between repeat A, repeat B, and repeat C sequences from different quasi-oligomeric PRE1. π, nucleotide diversity; r, Pearson’s correlation coefficient. T test, the P values of paired T tests of genetic distances among quasi-oligomeric PRE1 in three direct repeats
Fig. 5
Fig. 5
Methylation levels of proximal PRE1 correlate with the expression levels of the neighboring genes. a Distribution of methylation levels of proximal PRE1 copies. The dotted lines represent the overall average in muscle and testes. b PCA based on the methylation levels of proximal PRE1 in muscle and testes. c Global methylation level of proximal PRE1 of individuals. d Differentially-expressed genes between muscle and testes related to the mean methylation levels of proximal PRE1
Fig. 6
Fig. 6
Proximal PRE1 as a cis-regulatory element. a Differentially-methylated PRE1 and H3K27ac signals in the promoter of the TCEA3 gene. b–d Epigenetic and expressed signals in the TCEA3, HACD3 and HORMAD1 genes. e, f Number of PRE1 and differentially methylated PRE1 copies in intragenic, proximal, and distal regions. Proximal PRE1 and distal PRE1 were defined as those that are 1 to 2 kb and 2 to 100 kb upstream of their flanking genes, respectively
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