alexa Comparative and Evolutionary Studies of Vertebrate Arylsulfatase B, Arylsulfatase I and Arylsulfatase J Genes and Proteins: Evidence for an ARSB-like Sub-family
ISSN: 0974-276X
Journal of Proteomics & Bioinformatics

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Comparative and Evolutionary Studies of Vertebrate Arylsulfatase B, Arylsulfatase I and Arylsulfatase J Genes and Proteins: Evidence for an ARSB-like Sub-family

Roger S Holmes*

The Eskitis Institute for Drug Discovery and School of Natural Sciences, Griffith University, Nathan 4111 QLD, Australia

*Corresponding Author:
Roger S Holmes
The Eskitis Institute for Drug Discovery and School of Natural Sciences
Griffith University, Nathan 4111 QLD, Australia
Tel: 61737355077
E-mail: [email protected]

Received Date: October 25, 2016; Accepted Date: November 18, 2016; Published Date: November 23, 2016

Citation: Holmes RS (2016) Comparative and Evolutionary Studies of Vertebrate Arylsulfatase B, Arylsulfatase I and Arylsulfatase J Genes and Proteins: Evidence for an ARSB-like Sub-family. J Proteomics Bioinform 9: 298-305. doi: 10.4172/jpb.1000418

Copyright: © 2016 Holmes RS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Multiple sulfatase genes have been reported on the human genome, including Arylsulfatase B (ARSB), Arylsulfatase I (ARSI) and Arylsulfatase J (ARSJ). ARSB is localized in lysosomes and catalyses the hydrolysis of chondroitin and dermatan sulfate groups. Bioinformatic analyses of vertebrate genomes were undertaken using known human ARSB, ARSI and ARSJ amino acid sequences to study the relatedness and evolution of these genes and proteins. Several domain regions and key residues were conserved including signal peptides, active site residues, metal (Ca2+) and substrate binding sequences, disulfide linkages and N-glycosylation sites. The genes were widely expressed in human tissues with highest levels in esophagus (ARSB), lung (ARSI) and fibroblast cells (ARSB). Human ARSB was larger in size (>200 kb) and contained 8 coding exons, whereas ARSI and ARSJ contained only 2 coding exons among all vertebrate genomes examined. CpG islands were located within the 5’ region of the human ARSB, ARSI and ARSJ genes. In addition, six and seven miR-binding sites were observed within the 3’-UTR of human ARSB and ARSJ genes, respectively. Phylogenetic analyses describe a proposal for a primordial invertebrate SUL-3 gene serving as an ancestor for unequal cross over events generating these three genes in vertebrate genomes.

Keywords

Arylsulfatase B; Arylsulfatase I; Arylsulfatase J; ARSB; ARSI; ARSJ; Vertebrate; Evolution; Phylogeny; Primordial gene; Signal peptide; Transmembranes; Ca2+ binding; Active site; N-glycosylation site; Gene duplication

Abbreviations

ARS: Arylsulfatase; STS: Sterylsulfatase; ARSD: Arylsulfatase D; ARSE: Arylsulfatase E, ARSF: Arylsulfatase F; ARSH: Arylsulfatase H; UCSC: University of Santa Cruz California; EC: Enzyme Commission; BLAST: Basic Local Alignment Search Tool; BLAT: Blast-Like Alignment Tool; NCBI: National Center for Biotechnology Information; AceView: NCBI Based representation of public mRNAs; TFBS: Transcription Factor Binding Sites; UTR: Untranslated Gene Region; CpG: Region of high density of guaninecytosine dinucleotides; mRNA: Messenger RNA

Introduction

Arylsulfatase B (ARSB) is localized in mammalian lysosomes and shown to hydrolyze sulfate groups of N-acetyl-D-galactosamine-4- sulfate, chondroitin sulfate and dermatan sulfate [1-2]. Mammalian ARSB has a distinct but related amino acid sequence to other mammalian sulfatases, including Arylsulfatase A (ARSA) [3]; Arylsulfatase G (ARSG) [4]; Arylsulfatase K (ARSK) [5]; Sterylsulfatase (STS) and other members of a closely related group of arylsulfatases encoded on the mammalian X-chromosome (ARSD, ARSE, ARSF and ARSH) [6,7]. Other human sulfatases have been reported with related sequences, including Arylsulfatase I (ARSI) [8], Arylsulfatase J (ARSJ) [5], N-acetylgalactosamine-6-sulfatase (GALNS) [9]; N-acetylglucosamine-6-sulfatase (GNS) [10]; Iduronate-2-sulfatase (IDS) [11]; Heparan N-sulfatase (SGSH) [12]; and extracellular sulfatases (SULF1; SULF2) [13]. Sulfatase Modifying Factor 1 (SUMF1) plays an essential post-translational role by modifying the active site cysteine residue which is required for all of these sulfatases [5].

The structure for the Arylsulfatase B gene (ARSB) has been determined [14] and a lysosomal storage disease (Mucopolysaccharidosis VI, MPS6 or Maroteaux-Lamy syndrome) described with autosomal recessive inheritance associated with ARSB genetic variants [15,16].Clinical features for MPS6 may include skeletal malformations, corneal clouding, stiff joints, short stature and cardiac abnormalities [17]. In addition, clinical variation of ARSB gene expression regulates colonic epithelial cell migration and cell adhesion [18], consistent with the extra-lysosomal localization of ARSB within nuclear and cell membranes [19]. Moreover, ARSB has been shown to regulate neurite outgrowth and neuronal plasticity in the central nervous system, by way of controlling sulfate glycosaminoglycans and neurocan levels [20]. Defiency of ARSB has been implicated in the restriction of aerobic metabolism during malignancy, given that molecular oxygen is required for the post-translational modification of ARSB by SUMF1 [21]. The 3D structure for human ARSB has been determined showing sequence similarity with other sulfatases, with a common domain like structure supporting an active site involved in stabilizing calcium ion and sulfate substrate binding for catalytic sulfate ester hydrolysis [22].

This study describes the predicted sequences, structures and phylogeny of vertebrate ARSB, ARSI and ARSJ genes and enzymes and compares these results with those previously reported for human and mouse ARSB genes and proteins [1,2]. Evidence is presented on the sequences and properties of ARSB, ARSI and ARSJ from several vertebrate species and for distinct exonic structures and modes of gene regulation and expression, with the identification of CpG Island, miRComparative binding sites and transcription factor binding sites for these genes. Phylogenetic analyses also describe the relationships and potential origins of the ARSB, ARSI and ARSJ genes and enzymes during vertebrate evolution and a proposal for generating these genes from an ancestral invertebrate SUL-3 gene.

Materials and Methods

ARSB, ARSI and ARSJ gene and enzyme identification

Vertebrate ARSB, ARSI and ARSJ amino acid sequences were retrieved from databases (NCBI (http://blast.ncbi.nlm.nih.gov/Blast.cgi) and ExPASy (http://www.expasy.org) [23]), using the corresponding human sequences to seed searches [1,5]. An invertebrate ARSB-like (SUL3) sequence was similarly obtained from a search of a worm (Caenorhabditis elegans) genome database (NCBI (http://blast.ncbi.nlm.nih.gov/Blast.cgi). Identification of these genes and proteins was based on high predictive scores (>850) and sequence coverage (>98%) for ARSB, ARSI and ARSJ proteome sequences in each case (Table 1). BLAT searches were performed using protein sequences to confirm the gene and enzyme sequences among the species examined using the UCSC Genome Browser [24]. Gene locations, predicted gene structures and protein subunit sequences were obtained for each gene and enzyme examined showing identity with the respective sequences (Table 1). Human ARSB, ARSI and ARSJ gene structures were obtained using the AceView web browser (http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/) [25]. Identification of potential gene regulatory sites, including transcription factor binding sites (TFBS), CpG islands and miRNA-binding sites within the respective gene regions, was undertaken using the UCSC Human Genome Browser [24].

Organism Species Gene Coding Exons
(strand)
Gene Size
bps
Gene
Location
GenBank
ID*
UNIPROT
ID
Amino
acids
Subunit
MW (pI)
Signal
Peptide
TM
Human Homo sapiens ARSB 8 (-ve) 204,849 5:780,762,223-782,810,071 NM_000046 P14518 533 59,687 (8.4) 1…36 na
Mouse Mus musculus Arsb 8 (+ve) 168,951 13:93,771,778-93,940,728 NM_009712 P50429 534 59,647 (6.8) 1…41 na
Opossum Monodelphis domestica ARSB 8 (+ve) 241,222 3:37,109,032-37,350,253 XP_001381590* F6X4S3 522 58,845 (6.3) 1…28 na
Chicken Gallus gallus ARSB 8 (+ve) 65,767 Z:22,361,300-22,427,066 XP_003642960* F1P099 528 58,446 (7.0) 1…35 na
Frog Xenopus tropicalis ARSB 8 (+ve) 61,650 ^KB021649:16,113,025-16,174,674 XP_002940244* F7DJE4 531 58,373 (5.9) 1…35 na
Zebrafish Danio rerio ARSB 8 (+ve) 149,457 21:130,641-280,097 XP_003200848* na 517 57,495 (6.1) 1…20 na
Human Homo sapiens ARSI 2 (-ve) 5,157 5:150,297,217-150,302,373 NM_001012301 Q5FYB1 569 64,030 (8.8) 1…23 na
Mouse Mus musculus Arsi 2 (+ve) 5,526 18:60,912,240-60,917,765 NM_001038499 Q32KI9 573 64,367 (8.5) 1…23 na
Opossum Monodelphis domestica ARSI 2 (-ve) 7,998 1:343,247,971-343,255,968 XP_001378869* F6RZZ5 584 65,872 (8.0) 1…21 na
Chicken Gallus gallus ARSI 2 (+ve) 3,008 13:12,503,423-12,506,430 XP_004945003* F1NQP9 574 65,069 (9.0) 1…18 na
Frog Xenopus tropicalis ARSI 2 (-ve) 13,694 ^KB021651:45,092,627-45,106,320 XP_002940132* F6ZR01 573 64,490 (8.9) 1…18 na
Zebrafish Danio rerio ARSI 2 (-ve) 3,756 21:44,004536-44,008,291 XP_692237* E7F908 568 64,875 (9.4) 1…16 na
Human Homo sapiens ARSJ 2 (-ve) 76,558 4:113,902,277-113,978,834 NM_024590 Q5FYB0 599 67,235 (9.2) na 24..44
Mouse Mus musculus Arsj 2 (+ve) 74,627 3:126,364,774-126,439,400 NM_173451 Q8BM89 598 67,354 (9.3) na 24..44
Opossum Monodelphis domestica ARSJ 2 (-ve) 133,705 5:67,618,341-67,752,045 XP_001365999* F7DM73 607 68,543 (9.3) na 24..44
Chicken Gallus gallus ARSJ 2 (+ve) 39,513 4:56,052,213-56,091,725 XP_420639* F1NH07 578 64,975 (9.2) 1…19 na
Frog Xenopus tropicalis ARSJ 2 (-ve) 30,946 ^KB021649:153,510,397-153,541,342 XP_002934299* F6XVC7 564 63,962 (9.0) 1…17 na
Zebrafish Danio rerio ARSJ 2 (+ve) 11,114 7:57,375,146-57,386,259 XP_688265* F1REG3 568 64,733 (9.2) 1…32 na
Worm C. elegans SUL-3 14 (-ve) 6,839 X:7,827,197-7,834,035 NM_001047767 H2KZF6 484 55,541 (9.1) 1…24 na

Table 1: Human ARSB, ARSI and ARSJ genes and enzymes.

Comparative human ARSB, ARSI and ARSJ gene expression

RNA-seq gene expression profiles across 53 selected tissues (or tissue segments) were examined from the public database for human ARSB, ARSI and ARSJ, based on expression levels for 175 individuals [26] (Data Source: GTEx Analysis Release V6p (dbGaP Accession phs000424.v6.p1) (http://www.gtex.org).

Predicted structures and properties of human ARSB, ARSI and ARSJ subunits

Predicted secondary and tertiary structures for human sequences were obtained using SWISS MODEL web tools [27]. The human ARSB tertiary structure (PDB:1FSU) [22] served as a reference for obtaining these structures, with modelled residue ranges of 42-533 for human ARSB; 44-524 for human ARSI; and 73-555 for human ARSJ. Predicted transmembrane structures for vertebrate ARSJ subunits were obtained using a web server (http://www.cbs.dtu.dk/services/TMHMM-2.0) provided by the Center for Biological Sequence Analysis of the Technical University of Denmark [28]. SignalP 3.0 web tools were used to predict the presence and location of signal peptide cleavage sites (http://www.cbs.dtu.dk/services/SignalP); and the NetNGlyc 1.0 server was used to predict potential N-glycosylation sites for vertebrate ARSB, ARSI and ARSJ subunits [29] (http://www.cbs.dtu.dk/services/NetNGlyc).

Amino acid sequence alignments and phylogenetic analyses

Alignments of human ARSB, ARSI, ARSJ, GNS, SULF1, IDS, ARSK, SGSH, ARSA, ARSG, STS, GALNS and C. elegans SUL3 sequences were undertaken using Clustal Omega, a multiple sequence alignment program [30] (Table 1 and Supplementary Table 1). Percentage identities were derived from the results of these alignments (Table 2). Phylogenetic analyses used several bioinformatic programs,coordinated using the http://www.phylogeny.fr/ bioinformatic portal, to enable alignment (MUSCLE), curation (Gblocks), phylogeny (PhyML) and tree rendering (TreeDyn), to reconstruct phylogenetic relationships [31]. Sequences were identified as vertebrate ARSB, ARSI and ARSJ members, as well as a proposed primordial C. elegans SUL3 gene and protein (Table 1).

  GNS SULF1 IDS ARSK SGSH ARSB ARSI ARSJ ARSA ARSG STS GALNS
GNS 100 38 22 22 22 20 22 22 22 19 22 22
SULF1 38 100 22 20 19 18 21 20 20 17 20 19
IDS 22 22 100 24 24 27 24 24 27 20 25 25
ARSK 22 20 24 100 23 21 20 21 24 20 24 21
SGSH 22 19 24 23 100 27 25 23 28 27 26 27
ARSB 20 18 27 21 27 100 55 54 30 26 31 30
ARSI 22 21 24 20 25 55 100 55 28 26 27 27
ARSJ 22 20 24 21 23 54 59 100 25 25 25 26
ARSA 22 20 27 24 28 30 28 25 100 39 36 35
ARSG 19 17 20 20 27 26 26 25 39 100 32 35
STS 22 20 25 24 26 31 27 26 36 32 100 34
GALNS 22 19 25 21 27 30 27 26 35 35 34 100

Table 2: Percentage sequence identities for human ARS-like proteins.

proteomics-bioinformatics-Amino-acid

Figure 1: Amino acid sequence alignments for human ARSB, ARSI and ARSJ sequences.

Results and Discussion

Percentage identities of human arylsulfatase amino acid sequences

Percentages of amino acid sequence identities for 12 human ARS enzyme subunits are presented in Table 2. The sulfatase genes examined are separately localized on the human genome, encoding enzyme subunits with distinct MWs, pI values and amino acid sequence lengths (Table 3). The human ARSB, ARSI and ARSK genes were located on human chromosome 5; the human SGSH and ARSG genes on human chromosome 17; and others on separate chromosomes, in each case. This is in contrast to multiple human STS-like genes, which are located in a tandem fashion on the X-chromosome: ARSD-ARSE-ARSHARSF, within a 200 kb gene cluster, encoding enzymes with ≥50% sequence identities (data not shown). Of particular interest to this study were the higher levels of sequence identities observed for the human ARSB, ARSI and ARSJ enzyme subunits, which showed ≥54% sequence identities, suggesting that these genes and proteins are members of a closely related ARSB-like sub-family of human sulfatases.

Human
Gene
Coding Exons
(strand)
Gene Size
bps
Gene
Location
GenBank
ID*
UNIPROT
ID
Amino
acids
Subunit
MW (pI)
ARSB 8 (-ve) 2,04,849 5:780,762,223-782,810,071 NM_000046 P14518 533 59,687 (8.4)
ARSI 2 (-ve) 5,157 5:150,297,217-150,302,373 NM_001012301 Q5FYB1 569 64,030 (8.8)
ARSJ 2 (-ve) 76,558 4:113,902,277-113,978,834 NM_024590 Q5FYB0 599 67,235 (9.2)
GNS 14 (-ve) 42,533 12:64,716,744-64,759,276 NM_002076 P15586 552 62,082 (8.6)
SULF1 18 (+ve) 74,885 8:69,563,976-69,638,860 NM_001128204 Q8IWU6 871 101,027 (9.2)
IDS 9 (-ve) 22,389 X:149,482,749-149,505,137 NM_000207 P22304 550 61,873 (5.2)
ARSK 8 (+ve) 48,245 5:95,555,279-95,603,523 NM_198150 Q6UWY0 536 61,450 (9.0)
SGSH 8 (-ve) 9,859 17:80,210,455-80,220,313 NM_000199 P51688 502 56,695 (6.5)
ARSA 8 (-ve) 2,626 22:50,625,148-50,627,773 NM_000487 P15289 507 53,588 (5.7)
ARSG 11 (+ve) 1,12,967 17:68,307,494-68,420,460 NM_001267727 Q96EG1 525 57,061 (6.2)
STS 10 (+ve) 97,065 X:7,253,194-7,350,258 NM_000351 P08842 583 65,492 (7.6)
GALNS 14 (-ve) 42,536 16:88,880,850-88,923,285 NM_000512 P34059 522 58,026 (6.3)

Table 3: Human ARS-like genes and proteins.

Alignments of human ARSB, ARSI and ARSJ amino acid sequences

Amino acid sequence alignments for human ARSB, ARSI and ARSJ sequences (Table 1) are shown in Figure 1. Comparisons of these sequences with the human ARSB sequence, for which the tertiary structure has been described (template pdb: 1FSU) [22], enabled prediction of secondary structures and likely key residues contributing to catalysis, structure and function for the ARSI and ARSJ proteins. Active site residues (human ARSB numbers used) binding calcium ions (Ca2+) [53Asp, 54Asp, 300Asp, 301Asn) or substrate (91Cys; 145Lys; 147His; 242His; 318Lys) were conserved. One of the conserved active site residues (75Cys) has been shown to undergo posttranslational modification by sulfatase modifying factor 1 (SUMF1) to form C(alpha)-formylglycine (Fgly), which is required at the active site for all of these sulfatases [5]. Genetic deficiency of SUMF1 results in multiple sulfatase deficiency (MSD) [32].

Signal peptides of varying lengths were predicted for the vertebrate ARSB, ARSI and ARSJ sequences, which were consistent with the reported N-linked glycosylation and membrane associations for ARSB within lysosomal membranes (Table 1) [1]. In contrast, mammalian ARSJ sequences did not contain a predicted signal peptide, although a transmembrane structure was observed for the extended N-terminal sequence (residues 24-44 for human ARSJ). Human ARSB contained 6 predicted N-glycosylation sites (Asn188, Asn279, Asn291, Asn366, Asn426 and Asn458) for which Asn279 and Asn291 were also shared with the human ARSI and ARSJ sequences (Figure 1). In contrast, human ARSI and ARSJ sequences exhibited two other predicted N-glycosylation sites (human ARSI sequence numbers used): Asn466 and Asn496 (Figure 1). Four Cys residues involved in disulfide bond formation for human ARSB [20] were also conserved in the ARSI and ARSJ sequences (human ARSB numbers used): Cys121←→Cys155; Cys181←→Cys192; whereas four other Cys residues within the ARSB structure were not conserved for the human ARSI and ARSJ sequences:Cys117←→Cys521; and Cys405←→Cys447 (Figure 1). A poly-Glu (acidic) region within the human ARSJ N-terminal sequence was observed (residues 51Glu-55Glu) (Figure 1), which was shared with other mammalian ARSJ sequences (results not shown). A poly-acidic amino acid sequence (Asp526-Glu527-Glu528-Glu529-Glu530- Glu531-Glu532-Glu533) was also found at the C-terminus end of the human ARSI sequence. In contrast, a region of poly-basic amino acid residues was observed for the human ARSJ C-terminus sequence: Lys571-Lys572-Gln573-Lys574-Lys575-Ser576-Lys575-Lys578- Lys579-Lys580-Lys581-Lys582-Gln583-Gln584-Lys585- (Figure 1). The roles for these regions of negative and positive charges for the C-termini of the ARSI and ARSJ sequences remain to be determined, however it is likely that specific protein-protein binding may be assisted by these regions, in a similar way to that previously reported for glycosylphosphatidylinositol-anchored high density lipoproteinbinding protein 1, which binds lipoprotein lipase via a poly-acidic amino acid sequence [33]. Alternatively, these C-terminal negative and positive regions may contribute to specific microlocalization properties for these enzymes or to ARSI-ARSJ associations in forming dimeric hybrid enzymes, in vivo.

Predicted secondary structures for human ARSB, ARSI and ARSJ subunits are compared in Figure 1. Similar structures were observed for each of the enzymes examined, with the exception of the number of the signal peptide and transmembrane structures observed, previously discussed. Supplementary Figure 1 provides a 3-dimensional model for human ARSB which is based on the structure previously described by Bond and coworkers [22]. This shows a cleft, with the active site region located within an enzyme cavity containing a metal (Ca2+) ion on the ARSB surface at the carboxyl end of the central parallel portion of the β sheet. The enzyme has 2 domains, with the active site at the base of a cleft on the larger domain. Predicted 3D structures for human ARSI and ARSJ sequences were also undertaken (results not shown) which showed similar results for each of these enzymes.

Predicted gene locations and exonic structures for ARSB, ARSI and ARSJ genes and proteins

Table 1; Figures 1 and 2 summarize the predicted locations, sizes and number of coding exons for vertebrate ARSB, ARSI and ARSJ genes examined, and of the encoded human ARSB, ARSI and ARSJ subunit amino acid sequences. These were based on BLAST interrogations of vertebrate gene databases (http://blast.ncbi.nlm.nih.gov/Blast.cgi) using the reported sequences for human ARSB [1], ARSI [8] and ARSJ [5], and BLAT analyses of vertebrate genomes using the UC Santa Cruz Genome Browser (http://genome.ucsc.edu/cgi-bin/hgBlat) [24]. Vertebrate ARSB genes contained 8 coding exons and were larger in size (61-241 kb), whereas vertebrate ARSI and ARSJ genes contained only 2 coding exons and were smaller in size (3-14 kb and 11-133 kb, respectively), in each case (Table 1).

Table 1 show comparative locations, gene sizes and coding exon compositions for vertebrate ARSB, ARSI and ARSJ genes and a worm (C. elegans) ARSB-like gene (SUL-3), as well as comparative protein structures for the enzyme subunits. As can be seen, the three ARSB-like genes are widely separately on chromosomes for all species examined which may reflect the antiquity of these genes among the vertebrate genomes examined. Figure 1 summarizes the predicted exonic start sites for human ARSB, ARSI and ARSJ genes with ARSB having 8 exons, whereas ARSI and ARSJ contained only 2 coding exons. Of particular interest to this comparison was the similar positioning for the exon 2 start site for each of these genes, which may reflect a common evolutionary origin for this site within these genes.

Figure 2 presents diagrams for the major isoforms for human ARSB, ARSI and ARSJ genes, showing comparative locations and sizes for introns and exons, and for 5’- and 3’-UTR regions. As can be seen, the human ARSB gene is >30 times larger than the human ARSI gene and 2.6 times larger than the ARSJ gene, predominantly due to fewer exons being present for the latter genes (2 exons compared with 8 exons for ARSB). The human ARSB gene promoter contained a CpG island (CpG93) [34] and two predicted TFBS: ZBTB6, which encodes a Zinc finger and BTB domain-containing protein 6 which mediates transcriptional repression [35]; and CEBPA or CCAAT/ enhancer-binding protein alpha, a transcription factor that coordinates differentiation of hepatocytes, adipocytes, myeloid progenitors and cells of the placenta and lung [36]. Six microRNA sites were also located in the 3’-UTR of human ARSB, which are potentially of major significance for the regulation of this gene (Figure 2). A recent study of miR-590 has shown that it regulates osteogenic differentiation in developing human mesenchymal cells [37]. In addition, miR-24 functions as a tumor suppressor in nasopharangeal carcinoma [38]; miR-29 promotes Type II cell differentiation in the developing lung [39]; miR-346 regulates osteogenic differentiation of human bone marrow-derived mesenchymal stem cells [40]; and miR-203 suppresses cell proliferation, migration and invasion in colorectal cancer [41].

proteomics-bioinformatics-major-human-genes

Figure 2: Gene structures and major gene transcripts for the human ARSB, ARSI and ARSJ genes.

The ARSI gene promoter contained a CpG71 island although no predicted TFBS were detected in this region, and no miR-binding sites were observed in the ARSI 3’-UTR. The ARSJ gene promoter contained a CpG41 island and a predicted TFBS (E2F1), which represses transcriptional activity and may block adipocyte differentiation [41]. Seven miRNA binding regions were predicted in the 3’-UTR of the human ARSJ gene: miR-181 which functions as a tumor suppressor in non-small cell lung cancer [42]; miR-17-5p, which is strongly expressed in embryonic stem cells and has essential roles in cell cycle regulation, proliferation and apoptosis [43]; miR-181:1, which may act as a tumor suppressor in the pathogenesis of acute myeloid leukemia [44]; miR- 34a, which inhibits breast cancer proliferation [45]; miR-10, which participates in the regulation of Hox gene developmental regulators [46]; miR-133, recognized as a biomarker for lung cancer [47]; and miR-96, which promotes the growth of prostate carcinoma cells [48].

Comparative ARSB, ARSI and ARSJ human tissue expression

Figure 3 shows comparative gene expression for various human tissues obtained from RNA-seq gene expression profiles for human ARSB, ARSI and ARSJ genes obtained for 53 selected tissues or tissue segments for 175 individuals [26] (Data Source: GTEx Analysis Release V6p (dbGaP Accession phs000424.v6.p1) (http://www.gtex.org). These data supported a wide tissue expression profile for the 3 genes,with highest levels for human ARSB observed in the esophagus and transformed fibroblasts; the highest ARSI gene expression level was observed in lung and the tibial nerve; whereas highest ARSJ expression was seen in transformed fibroblasts.

proteomics-bioinformatics-tissue-human

Figure 3: Comparative tissue expression for human ARSB, ARSI and ARSJ genes.

Phylogeny and evolution of vertebrate ARSB, ARSI and ARSJ sequences

A phylogram (Figure 4) was calculated by the progressive alignment of vertebrate ARSB, ARSI, and ARSJ amino acid sequences, using a worm SUL-3 sequence (from C. elegans) (Table 1) to ‘root’ the tree. Homolog sequences were identified for all vertebrate genomes examined. The phylogram demonstrates separation of these sequences into three distinct groups consistent with their relatedness during vertebrate evolution, and suggests that these genes have been derived from an ancestral invertebrate SUL-3 gene.

proteomics-bioinformatics-Phylogenetic-tree

Figure 4: Phylogenetic tree for vertebrate and invertebrate ARSB, ARSI and ARSJ sequences.

Figure 4 also summarizes a working hypothesis for the evolution of vertebrate ARSB-like gene genes:

1. A proposed primordial invertebrate ARSB-like gene (SUL-3) was derived from a bacterial ancestor.

2. A proposed vertebrate ARSB ancestral gene containing 8 coding exons was inherited from a primordial vertebrate ancestor.

3. Following cDNA formation, a 2 exon transcript was retrointegrated into an ancestral vertebrate genome, forming an ancestral ARSI-ARSJ primordial gene.

4. A gene duplication event generated 2 separate lines of evolution: ARSI and ARSJ genes, which underwent sequence divergence and separate integration into the vertebrate genome.

Conclusion

BLAST and BLAT analyses of veretebrate genome databases were undertaken using amino acid sequences reported for human ARSB for interrogation of vertebrate genome sequences and an invertebrate genome (Sul-3) sequence (C. elegans). Predicted amino acid sequences for these vertebrate ARSB, ARSI and ARSJ subunits showed a high degree of sequence identity (>54% identical). Secondary structure and key residue identification were undertaken using a previous report for human ARSB 3D structure [22], which enabled identification of putative secondary structures and likely key residues contributing to catalysis, structure and function.

Bioinformatic analyses enabled the identification of putative gene regulation sites, including CpG islands, TFBS and miR-binding sites, for the promoter and 3’-UTR regions for the human ARSB, ARSI and ARSJ genes examined. These included CpG93, CpG71 and CpG41 localized within the human ARSB, ARSI and ARSJ gene promoter region; and 13 miR-binding sites, including miR-590 (for ARSB 3’-UTR) which regulates osteogenic differentiation in developing human mesenchymal cells [37]; and miR-10, which participates in the regulation of Hox gene developmental regulators [46].

Phylogenetic analyses suggested that vertebrate ARSB, ARSI and ARSJ genes were derived from an initial gene duplication event of a primordial invertebrate Sul-3 gene, generating 2 sub-families: ARSB and ARSI/ARSJ genes, with the latter containing only 2 coding exons, in comparison with the vertebrate ancestral ARSB gene, containing 8 coding exons.

Acknowledgements

I thank Dr Laura Cox from the Texas Biomedical Research Institute for useful discussions. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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