Novel Role of the ALPI Gene Associated with Constipation Caused by Complement Component 3 Deficiency
Abstract
:1. Introduction
2. Results
2.1. Verification of C3 Deficiency-Induced Constipation in C3 KO Mice
2.2. Characterization of the Changes in the Global Gene Expression Using the Mid Colon Tissue in C3 Deficiency-Induced Constipation
2.3. Reliability of the Expression of Differential Genes Detected in the Microarray Analysis
2.4. Biological Functions of Genes Associated with C3 Deficiency-Induced Constipation
2.5. Selection of the ALPI Gene as a New Treatment Target for C3 Deficiency-Induced Constipation and Verification of Its Function in Acetate-Treated Epithelial Cells
2.6. Verification of the ALPI Gene as a New Treatment Target for C3 Deficiency-Induced Constipation in Acetate-Treated C3 KO Mice
3. Discussion
4. Materials and Methods
4.1. Animal Care and Use
4.2. Experimental Designs of C3 KO Mice for Microarray Analyses
4.3. Experimental Designs for the Acetate Treatment of C3 KO Mice
4.4. Analyses of the Stool Parameters
4.5. GI Motility Analysis
Total intestine length] × 100
4.6. Histopathological Analysis
4.7. Quantitative Real-Time PCR (RT-qPCR) Analysis
4.8. Western Blot Analysis
4.9. Microarray Analysis
4.10. Acetate Treatment of Epithelial Cells Derived from the Colon of C3 KO Mice
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Categories | Number of Transcripts | Fold Change | |
---|---|---|---|
Total | 41,345 | ||
Filtered gene | 33,793 | ||
┃Fold change┃≥ 1.5 and raw. p < 0.05 | 2529 | Up | 1237 |
Down | 1292 | ||
┃Fold change┃≥ 2.0 and raw. p < 0.05 | 455 | Up | 226 |
Down | 229 | ||
┃Fold change┃≥ 3.0 and raw. p < 0.05 | 110 | Up | 38 |
Down | 72 |
Category Term | Count |
---|---|
Upregulated genes | |
Biological regulation | 13 |
Cell periphery | 11 |
Cellular anatomical entity | 5 |
Extracellular region | 5 |
G protein-coupled receptor signaling pathway | 1 |
Membrane | 5 |
Molecular transducer activity | 16 |
Molecular function | 2 |
Multicellular organismal process | 1 |
Odorant binding | 6 |
Peptidase activity | 2 |
Response to chemical | 21 |
Response to stimulus | 1 |
System process | 6 |
tRNA dihydrouridine synthase activity | 1 |
Immunoglobulin chain | 30 |
Predicted gene | 84 |
Blank | 16 |
Downregulated genes | |
Biological regulation | 8 |
Cation binding | 1 |
Cell periphery | 21 |
Cellular anatomical entity | 2 |
Extracellular region | 18 |
G protein-coupled receptor signaling pathway | 4 |
Hydrolase activity | 3 |
Intermediate filament | 1 |
Membrane | 9 |
Molecular transducer activity | 20 |
Molecular function | 7 |
Multicellular organismal process | 2 |
Organic acid binding | 1 |
Response to chemical | 22 |
Response to stimulus | 6 |
System process | 9 |
Keratin filament | 1 |
Predicted gene | 50 |
Immunoglobulin chain | 23 |
Blank | 21 |
Total | 455 |
Gene Symbol | Gene Name | Accession No. | Fold of Change | GO Category |
---|---|---|---|---|
Eif2s3y | eukaryotic translation initiation factor 2, subunit 3, structural gene Y-linked | NM_012011 | 29.68 | Mus musculus eukaryotic translation initiation factor 2, subunit 3, structural gene Y-linked (Eif2s3y), mRNA |
Uty | ubiquitously transcribed tetratricopeptide repeat gene, Y chromosome | NM_009484 | 24.65 | Mus musculus ubiquitously transcribed tetratricopeptide repeat gene, Y chromosome (Uty), mRNA |
Kdm5d | lysine (K)-specific demethylase 5D | NM_011419 | 19.14 | Mus musculus lysine (K)-specific demethylase 5D (Kdm5d), mRNA |
Igkv6-32 | immunoglobulin kappa variable 6-32 | OTTMUST00000132971 | 7.94 | immunoglobulin kappa variable 6-32[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Ighv1-80 | immunoglobulin heavy variable 1-80 | OTTMUST00000131491 | 7.28 | immunoglobulin heavy variable 1-80[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Igkv4-90 | immunoglobulin kappa chain variable 4-90 | OTTMUST00000132285 | 6.53 | immunoglobulin kappa chain variable 4-90[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Igkv5-48 | immunoglobulin kappa variable 5-48 | OTTMUST00000132845 | 6.43 | immunoglobulin kappa variable 5-48[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Ighv8-5 | immunoglobulin heavy variable V8-5 | OTTMUST00000131047 | 6.37 | immunoglobulin heavy variable V8-5[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Olfr870 | olfactory receptor 870 | NM_146904 | 5.71 | Mus musculus olfactory receptor 870 (Olfr870), mRNA |
Ddx3y | DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked | NM_012008 | 5.65 | Mus musculus DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, Y-linked (Ddx3y), mRNA |
Gm26194 | predicted gene, 26194 [Source:MGI Symbol;Acc:MGI:5455971] | ENSMUST00000175036 | 5.57 | predicted gene, 26194 [gene_biotype:miRNA transcript_biotype:miRNA] |
Igkv8-30 | immunoglobulin kappa chain variable 8-30 | OTTMUST00000133006 | 5.42 | immunoglobulin kappa chain variable 8-30[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Igkv8-21 | immunoglobulin kappa variable 8-21 | OTTMUST00000133067 | 4.82 | immunoglobulin kappa variable 8-21[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Igkv3-7 | immunoglobulin kappa variable 3-7 | OTTMUST00000133340 | 4.71 | immunoglobulin kappa variable 3-7[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Gm23479 | predicted gene, 23479 [Source:MGI Symbol;Acc:MGI:5453256] | ENSMUST00000158876 | 4.20 | predicted gene, 23479 [gene_biotype:snoRNA transcript_biotype:snoRNA] |
Serpina1c | serine (or cysteine) peptidase inhibitor, clade A, member 1C | NM_009245 | 4.19 | Mus musculus serine (or cysteine) peptidase inhibitor, clade A, member 1C (Serpina1c), mRNA |
Hoxd13 | homeobox D13 | NM_008275 | 4.18 | Mus musculus homeobox D13 (Hoxd13), mRNA |
Gm25897 | predicted gene, 25897 [Source:MGI Symbol;Acc:MGI:5455674] | ENSMUST00000083709 | 4.02 | predicted gene, 25897 [gene_biotype:snRNA transcript_biotype:snRNA] |
Gpx2 | glutathione peroxidase 2 | NM_030677 | 3.92 | Mus musculus glutathione peroxidase 2 (Gpx2), mRNA |
Ighm | immunoglobulin heavy constant mu | AF321953 | 3.79 | Mus musculus BW2 24-13 immunoglobulin heavy chain mRNA, partial cds |
Gm24032 | predicted gene, 24032 [Source:MGI Symbol;Acc:MGI:5453809] | ENSMUST00000083932 | 3.79 | predicted gene, 24032 [gene_biotype:snRNA transcript_biotype:snRNA] |
Ighv4-1 | immunoglobulin heavy variable 4-1 | OTTMUST00000130463 | 3.50 | immunoglobulin heavy variable 4-1[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Gm23280 | predicted gene, 23280 [Source:MGI Symbol;Acc:MGI:5453057] | ENSMUST00000157905 | 3.35 | predicted gene, 23280 [gene_biotype:snoRNA transcript_biotype:snoRNA] |
Gm22149 | predicted gene, 22149 [Source:MGI Symbol;Acc:MGI:5451926] | ENSMUST00000104442 | 3.33 | predicted gene, 22149 [gene_biotype:snoRNA transcript_biotype:snoRNA] |
Ifit3b | interferon-induced protein with tetratricopeptide repeats 3B | NM_001005858 | 3.31 | Mus musculus interferon-induced protein with tetratricopeptide repeats 3B (Ifit3b), mRNA |
ENSMUST00000106852 | 3.31 | predicted gene 10964 [gene_biotype:protein_coding transcript_biotype:protein_coding] | ||
Gm22305 | predicted gene, 22305 [Source:MGI Symbol;Acc:MGI:5452082] | ENSMUST00000082690 | 3.30 | predicted gene, 22305 [gene_biotype:snRNA transcript_biotype:snRNA] |
Igkv9-120 | immunoglobulin kappa chain variable 9-120 | OTTMUST00000131795 | 3.23 | immunoglobulin kappa chain variable 9-120[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Klra9 | killer cell lectin-like receptor subfamily A, member 9 | NM_010651 | 3.19 | Mus musculus killer cell lectin-like receptor subfamily A, member 9 (Klra9), mRNA |
1700054O19Rik | RIKEN cDNA 1700054O19 gene | XR_383299 | 3.17 | PREDICTED: Mus musculus RIKEN cDNA 1700054O19 gene (1700054O19Rik), misc_RNA |
2200002J24Rik | RIKEN cDNA 2200002J24 gene | XM_006540347 | 3.15 | PREDICTED: Mus musculus RIKEN cDNA 2200002J24 gene (2200002J24Rik), transcript variant X1, mRNA |
Ighm | immunoglobulin heavy constant mu | AF045497 | 3.09 | Mus musculus dC10 anti-poly(dC) monoclonal antibody heavy chain variable region, (IgH) mRNA, partial cds |
Gm22521 | predicted gene, 22521 [Source:MGI Symbol;Acc:MGI:5452298] | ENSMUST00000158272 | 3.08 | predicted gene, 22521 [gene_biotype:snoRNA transcript_biotype:snoRNA] |
Gm23626 | predicted gene, 23626 [Source:MGI Symbol;Acc:MGI:5453403] | ENSMUST00000082458 | 3.07 | predicted gene, 23626 [gene_biotype:snoRNA transcript_biotype:snoRNA] |
Gm26375 | predicted gene, 26375 [Source:MGI Symbol;Acc:MGI:5456152] | ENSMUST00000101829 | 3.03 | predicted gene, 26375 [gene_biotype:snRNA transcript_biotype:snRNA] |
Gm24555 | predicted gene, 24555 [Source:MGI Symbol;Acc:MGI:5454332] | ENSMUST00000104548 | 3.02 | predicted gene, 24555 [gene_biotype:snoRNA transcript_biotype:snoRNA] |
Olfr555 | olfactory receptor 555 | NM_147103 | 3.01 | Mus musculus olfactory receptor 555 (Olfr555), mRNA |
Gene Symbol | Gene Name | Accession No. | Fold of Change | GO Category |
---|---|---|---|---|
Pnlip | pancreatic lipase | NM_026925 | −658.36 | Mus musculus pancreatic lipase (Pnlip), mRNA. |
Cel | carboxyl ester lipase | NM_009885 | −476.60 | Mus musculus carboxyl ester lipase (Cel), mRNA. |
Cpb1 | carboxypeptidase B1 (tissue) | NM_029706 | −257.26 | Mus musculus carboxypeptidase B1 (tissue) (Cpb1), mRNA. |
Ctrl | chymotrypsin-like | NM_023182 | −214.25 | Mus musculus chymotrypsin-like (Ctrl), mRNA. |
2210010C04Rik | RIKEN cDNA 2210010C04 gene | NM_023333 | −208.33 | Mus musculus RIKEN cDNA 2210010C04 gene (2210010C04Rik), mRNA. |
Pnliprp1 | pancreatic lipase-related protein 1 | NM_018874 | −205.18 | Mus musculus pancreatic lipase-related protein 1 (Pnliprp1), mRNA. |
Reg1 | regenerating islet-derived 1 | NM_009042 | −187.41 | Mus musculus regenerating islet-derived 1 (Reg1), mRNA. |
Amy2a5 | amylase 2a5 | NM_001042711 | −183.01 | Mus musculus amylase 2a5 (Amy2a5), mRNA. |
Amy2a5 | amylase 2a5 | NM_001042711 | −167.12 | Mus musculus amylase 2a5 (Amy2a5), mRNA. |
Amy2a5 | amylase 2a5 | NM_001042711 | −162.29 | Mus musculus amylase 2a5 (Amy2a5), mRNA. |
Amy2a5 | amylase 2a5 | NM_001042711 | −162.29 | Mus musculus amylase 2a5 (Amy2a5), mRNA. |
Cpa1 | carboxypeptidase A1, pancreatic | NM_025350 | −158.70 | Mus musculus carboxypeptidase A1, pancreatic (Cpa1), mRNA. |
Rnase1 | ribonuclease, RNase A family, 1 (pancreatic) | NM_011271 | −146.66 | Mus musculus ribonuclease, RNase A family, 1 (pancreatic) (Rnase1), mRNA. |
Ctrb1 | chymotrypsinogen B1 | NM_025583 | −126.96 | Mus musculus chymotrypsinogen B1 (Ctrb1), mRNA. |
Cela2a | chymotrypsin-like elastase family, member 2A | NM_007919 | −114.78 | Mus musculus chymotrypsin-like elastase family, member 2A (Cela2a), mRNA. |
Prss2 | protease, serine 2 | NM_009430 | −94.18 | Mus musculus protease, serine 2 (Prss2), mRNA. |
Xist | inactive X-specific transcripts | NR_001463 | −92.79 | Mus musculus inactive X-specific transcripts (Xist), transcript variant 1, long non-coding RNA. |
Gm5409 | predicted pseudogene 5409 | NM_001003664 | −74.02 | Mus musculus predicted pseudogene 5409 (Gm5409), mRNA. |
Gp2 | glycoprotein 2 (zymogen granule membrane) | NM_025989 | −66.26 | Mus musculus glycoprotein 2 (zymogen granule membrane) (Gp2), mRNA. |
Amy2b | amylase 2b | NM_001190403 | −64.57 | Mus musculus amylase 2b (Amy2b), transcript variant 1, mRNA. |
Serpini2 | serine (or cysteine) peptidase inhibitor, clade I, member 2 | NM_026460 | −63.69 | Mus musculus serine (or cysteine) peptidase inhibitor, clade I, member 2 (Serpini2), mRNA. |
Pnliprp2 | pancreatic lipase-related protein 2 | NM_011128 | −55.74 | Mus musculus pancreatic lipase-related protein 2 (Pnliprp2), mRNA. |
Pdia2 | protein disulfide isomerase-associated 2 | NM_001081070 | −51.56 | Mus musculus protein disulfide isomerase-associated 2 (Pdia2), mRNA. |
Pla2g1b | phospholipase A2, group IB, pancreas | NM_011107 | −49.31 | Mus musculus phospholipase A2, group IB, pancreas (Pla2g1b), mRNA. |
Ctrc | chymotrypsin C (caldecrin) | NM_001033875 | −47.07 | Mus musculus chymotrypsin C (caldecrin) (Ctrc), mRNA. |
Prss1 | protease, serine 1 (trypsin 1) | NM_053243 | −44.45 | Mus musculus protease, serine 1 (trypsin 1) (Prss1), mRNA. |
Clps | colipase, pancreatic | NM_025469 | −42.88 | Mus musculus colipase, pancreatic (Clps), mRNA. |
Cela3b | chymotrypsin-like elastase family, member 3B | NM_026419 | −42.82 | Mus musculus chymotrypsin-like elastase family, member 3B (Cela3b), mRNA. |
Try4 | trypsin 4 | NM_011646 | −35.21 | Mus musculus trypsin 4 (Try4), mRNA. |
Cpa2 | carboxypeptidase A2, pancreatic | NM_001024698 | −32.13 | Mus musculus carboxypeptidase A2, pancreatic (Cpa2), mRNA. |
Olfr764-ps1 | olfactory receptor 764, pseudogene 1 | XM_887185 | −27.97 | PREDICTED: Mus musculus olfactory receptor 764 (Olfr764), mRNA. |
Cuzd1 | CUB and zona pellucida-like domains 1 | NM_008411 | −24.78 | Mus musculus CUB and zona pellucida-like domains 1 (Cuzd1), mRNA. |
Cckar | cholecystokinin A receptor | NM_009827 | −12.71 | Mus musculus cholecystokinin A receptor (Cckar), mRNA. |
Tff2 | trefoil factor 2 (spasmolytic protein 1) | NM_009363 | −10.82 | Mus musculus trefoil factor 2 (spasmolytic protein 1) (Tff2), mRNA. |
Cela1 | chymotrypsin-like elastase family, member 1 | NM_033612 | −9.61 | Mus musculus chymotrypsin-like elastase family, member 1 (Cela1), mRNA. |
Ang4 | angiogenin, ribonuclease A family, member 4 | NM_177544 | −8.63 | Mus musculus angiogenin, ribonuclease A family, member 4 (Ang4), mRNA. |
Tmed6 | transmembrane emp24 protein transport domain containing 6 | NM_025458 | −7.42 | Mus musculus transmembrane emp24 protein transport domain containing 6 (Tmed6), mRNA. |
Ighv1-67 | immunoglobulin heavy variable V1-67 | OTTMUST00000131282 | −7.09 | immunoglobulin heavy variable V1-67[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Reg3d | regenerating islet-derived 3 delta | NM_001161741 | −6.90 | Mus musculus regenerating islet-derived 3 delta (Reg3d), transcript variant 2, mRNA. |
Sptssb | serine palmitoyltransferase, small subunit B | NM_001164210 | −6.68 | Mus musculus serine palmitoyltransferase, small subunit B (Sptssb), transcript variant 1, mRNA. |
Vtn | vitronectin | NM_011707 | −5.72 | Mus musculus vitronectin (Vtn), mRNA. |
Tmed11 | transmembrane emp24 protein transport domain containing | NM_026109 | −5.08 | Mus musculus transmembrane emp24 protein transport domain containing (Tmed11), mRNA. |
Igkv6-17 | immunoglobulin kappa variable 6-17 | OTTMUST00000133153 | −5.08 | immunoglobulin kappa variable 6-17[gene_biotype:IG_gene transcript_biotype:IG_gene] |
Aqp12 | aquaporin 12 | NM_001159658 | −4.75 | Mus musculus aquaporin 12 (Aqp12), transcript variant 2, mRNA. |
1810007D17Rik | RIKEN cDNA 1810007D17 gene | NR_038136 | −4.75 | Mus musculus RIKEN cDNA 1810007D17 gene (1810007D17Rik), long non-coding RNA. |
Try5 | trypsin 5 | NM_001003405 | −4.59 | Mus musculus trypsin 5 (Try5), mRNA. |
Plet1 | placenta expressed transcript 1 | NM_029639 | −4.51 | Mus musculus placenta expressed transcript 1 (Plet1), mRNA. |
Try10 | trypsin 10 | NM_001038996 | −4.38 | Mus musculus trypsin 10 (Try10), mRNA. |
B3gnt6 | UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 6 (core 3 synthase) | NM_001081167 | −4.20 | Mus musculus UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 6 (core 3 synthase) (B3gnt6), mRNA. |
Itln1 | intelectin 1 (galactofuranose binding) | NM_010584 | −4.04 | Mus musculus intelectin 1 (galactofuranose binding) (Itln1), mRNA. |
Ighg | Immunoglobulin heavy chain (gamma polypeptide) | AB097847 | −3.89 | Mus musculus mRNA for immunoglobulin gamma-2a heavy chain, complete cds, anti-malathion monoclonal antibody MLT2-23. |
Igkv3-4 | immunoglobulin kappa variable 3-4 | OTTMUST00000133343 | −3.82 | immunoglobulin kappa variable 3-4[gene_biotype:IG_gene transcript_biotype:IG_gene] |
GENSCAN00000010106 | −3.75 | cdna:genscan chromosome:GRCm38:19:28745871:28759892:-1 transcript_biotype:protein_coding | ||
Gm25720 | predicted gene, 25720 [Source:MGI Symbol;Acc:MGI:5455497] | ENSMUST00000157503 | −3.72 | predicted gene, 25720 [gene_biotype:snRNA transcript_biotype:snRNA] |
Gm26441 | predicted gene, 26441 [Source:MGI Symbol;Acc:MGI:5456218] | ENSMUST00000082590 | −3.54 | predicted gene, 26441 [gene_biotype:snRNA transcript_biotype:snRNA] |
Chst2 | carbohydrate sulfotransferase 2 | NM_018763 | −3.24 | Mus musculus carbohydrate sulfotransferase 2 (Chst2), mRNA. |
Vmn2r57 | vomeronasal 2, receptor 57 | NM_177764 | −3.22 | Mus musculus vomeronasal 2, receptor 57 (Vmn2r57), mRNA. |
Fabp2 | fatty acid-binding protein 2, intestinal | NM_007980 | −3.20 | Mus musculus fatty acid-binding protein 2, intestinal (Fabp2), mRNA. |
NONMMUT000288 | −3.20 | Non-coding transcript identified by NONCODE | ||
Isx | intestine-specific homeobox | NM_001294278 | −3.15 | Mus musculus intestine-specific homeobox (Isx), transcript variant 1, mRNA. |
Klk1b27 | kallikrein 1-related peptidase b27 | NM_020268 | −3.09 | Mus musculus kallikrein 1-related peptidase b27 (Klk1b27), mRNA. |
Psg25 | pregnancy-specific glycoprotein 25 | NM_054060 | −3.06 | Mus musculus pregnancy-specific glycoprotein 25 (Psg25), mRNA. |
Gm24762 | predicted gene, 24762 [Source:MGI Symbol;Acc:MGI:5454539] | ENSMUST00000083689 | −3.02 | predicted gene, 24762 [gene_biotype:snRNA transcript_biotype:snRNA] |
Ero1lb | ERO1-like beta (S. cerevisiae) | NM_026184 | −3.02 | Mus musculus ERO1-like beta (S. cerevisiae) (Ero1lb), mRNA. |
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Song, H.J.; Kim, J.E.; Roh, Y.J.; Seol, A.; Kim, T.R.; Park, K.H.; Park, E.S.; Hong, J.T.; Choi, S.I.; Hwang, D.Y. Novel Role of the ALPI Gene Associated with Constipation Caused by Complement Component 3 Deficiency. Int. J. Mol. Sci. 2024, 25, 9530. https://doi.org/10.3390/ijms25179530
Song HJ, Kim JE, Roh YJ, Seol A, Kim TR, Park KH, Park ES, Hong JT, Choi SI, Hwang DY. Novel Role of the ALPI Gene Associated with Constipation Caused by Complement Component 3 Deficiency. International Journal of Molecular Sciences. 2024; 25(17):9530. https://doi.org/10.3390/ijms25179530
Chicago/Turabian StyleSong, Hee Jin, Ji Eun Kim, Yu Jeong Roh, Ayun Seol, Tae Ryeol Kim, Ki Ho Park, Eun Seo Park, Jin Tae Hong, Sun Il Choi, and Dae Youn Hwang. 2024. "Novel Role of the ALPI Gene Associated with Constipation Caused by Complement Component 3 Deficiency" International Journal of Molecular Sciences 25, no. 17: 9530. https://doi.org/10.3390/ijms25179530