Generic placeholder image

Cardiovascular & Hematological Disorders-Drug Targets

Author(s): Fatemeh Movahedi Motlagh, Hamid Reza Soleimanpour-Lichaei, Ali Emami, Sepideh Kadkhoda, Mehdi Shamsara, Azam Rasti and Mohammad Hossein Modarressi*

DOI: 10.2174/1871529X22666220617125731

DownloadDownload PDF Flyer Cite As
Bcl11a and the Correlated Key Genes Ascribable to Globin Switching: An In-silico Study

Page: [128 - 142] Pages: 15

  • * (Excluding Mailing and Handling)

Abstract

Background: Reactivation of HbF is a potential strategy to ameliorate symptoms of hemoglobinopathies such as sickle cell disease and b-thalassemia. After birth, there is a switch from fetal to adult hemoglobin, for which the molecular mechanisms and key regulators await further understanding in order to develop effective methods for HbF reactivation. Bcl11a, one of the major HbF reactivation regulators, demonstrates no significant changes at transcriptional levels in F erythroblasts compared to the non-HbF expressing cells. Therefore, it is possible that posttranscriptional regulation and epigenetic effects, for which the miRNAs play an important role, are the primary causes of the decreased Bcl11a protein level in adult erythroblasts.

Objective: This paper aims to determine the differentially expressed mRNAs and miRNAs of erythroblasts in HSCs from the fetal liver and bone marrow.

Methods: Raw high-throughput sequencing data (GSE110936, GSE90878) was downloaded from Gene Expression Omnibus (GEO) database. After RNAseq analysis, several data sets and tools were used to select key genes and examine selection validation.

Results: We selected 42 DEmRNAs and nine DEmiRs, including hsa-let-7f-5p, hsa-miR-21-5p, hsamiR- 22-3p, hsa-miR-126-5p, hsa-miR-146b-5p, hsa-miR-181a-5p, hsa-miR-92a-3p, hsa-miR-25-3p and hsa-miR-191-5p. Furthermore, hub genes including hist1h2bl, al133243.2, trim58, abcc13, bpgm, and fam210b were identified in the coexpression network, as well as RPS27A in the PPI network. Functional analysis revealed that these DEmRNAs and DEmiRs might play a role in gene expression regulation at multiple levels. Gene set enrichment analysis, in particular, revealed a possible role for genes in the globin switching process.

Conclusion: According to our findings, a number of the DEmRNAs and DEmiRs may play significant roles in globin switching regulation and thus have the potential to be applied for HbF reactivation.

Keywords: In-silico study, systems biology, differentially expressed mRNAs, miRNAs, fetal and adult erythroblasts, globin switching

Graphical Abstract

[1]
Saki, N.; Abroun, S.; Soleimani, M.; Kavianpour, M.; Shahjahani, M.; Mohammadi-Asl, J.; Hajizamani, S. MicroRNA expression in β-thalassemia and sickle cell disease: A role in the induction of fetal hemoglobin. Cell J., 2016, 17(4), 583-592.
[PMID: 26862517]
[2]
Azzouzi, I.; Schmugge, M.; Speer, O. MicroRNAs as components of regulatory networks controlling erythropoiesis. Eur. J. Haematol., 2012, 89(1), 1-9.
[http://dx.doi.org/10.1111/j.1600-0609.2012.01774.x] [PMID: 22372390]
[3]
Lulli, V.; Romania, P.; Morsilli, O.; Cianciulli, P.; Gabbianelli, M.; Testa, U.; Giuliani, A.; Marziali, G. MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating Bcl11a. PLoS One, 2013, 8(4), e60436.
[http://dx.doi.org/10.1371/journal.pone.0060436] [PMID: 23593217]
[4]
Liu, N.; Hargreaves, V.V.; Zhu, Q.; Kurland, J.V.; Hong, J.; Kim, W. Direct promoter repression by Bcl11a controls the fetal to adult hemoglobin switch. Cell, 2018, 173(2), 430-442.
[http://dx.doi.org/10.1016/j.cell.2018.03.016]
[5]
Das, S.S.; Das, S.; Byram, P.K.; Rahaman, M.; Dolai, T.K.; Chatterjee, A.; Chakravorty, N. MicroRNA expression patterns in HbE/β-thalassemia patients: The passwords to unlock fetal hemoglobin expression in β-hemoglobinopathies. Blood Cells Mol. Dis., 2021, 87, 102523.
[http://dx.doi.org/10.1016/j.bcmd.2020.102523] [PMID: 33242839]
[6]
Yaghoobi, H.; Babaei, E.; Hussen, B.M.; Emami, A. EBST: An evolutionary multi-objective optimization based tool for discovering potential biomarkers in ovarian cancer. IEEE/ACM Trans. Comput. Biol. Bioinformatics, 2020, 18(6), 2384-2393.
[7]
Wasserman, P.D. Advanced methods in neural computing; John Wiley & Sons, Inc., 1993.
[8]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[9]
Vejnar, C.E.; Zdobnov, E.M. MiRmap: comprehensive prediction of microRNA target repression strength. Nucleic Acids Res., 2012, 40(22), 11673-11683.
[http://dx.doi.org/10.1093/nar/gks901] [PMID: 23034802]
[10]
Agarwal, V; Bell, GW; Nam, J-W Bartel, DP Predicting effective microRNA target sites in mammalian mRNAs. elife, 2015, 4, e05005.
[11]
Karagkouni, D.; Paraskevopoulou, M.D.; Chatzopoulos, S.; Vlachos, I.S.; Tastsoglou, S.; Kanellos, I.; Papadimitriou, D.; Kavakiotis, I.; Maniou, S.; Skoufos, G.; Vergoulis, T.; Dalamagas, T.; Hatzigeorgiou, A.G. DIANA-TarBase v8: A decade-long collection of experimentally supported miRNA-gene interactions. Nucleic Acids Res., 2018, 46(D1), D239-D245.
[http://dx.doi.org/10.1093/nar/gkx1141] [PMID: 29156006]
[12]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[13]
Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102.
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[14]
Salavaty, A.; Motlagh, F.M.; Barabadi, M.; Cheshomi, H.; Esmatabadi, M.J.D.; Shahmoradi, M.; Soleimanpour-Lichaei, H.R. Potential role of RAB6C-AS1 long noncoding RNA in different cancers. J. Cell. Physiol., 2018, 234(1), 891-903.
[http://dx.doi.org/10.1002/jcp.26910] [PMID: 30076712]
[15]
Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C.V. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res., 2019, 47(D1), D607-D613.
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[16]
Supek, F.; Bošnjak, M.; Škunca, N.; Šmuc, T. REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One, 2011, 6(7), e21800.
[http://dx.doi.org/10.1371/journal.pone.0021800] [PMID: 21789182]
[17]
Wang, J.; Li, M.; Chen, J.; Pan, Y. A fast hierarchical clustering algorithm for functional modules discovery in protein interaction networks. IEEE/ACM Trans. Comput. Biol. Bioinformatics, 2011, 8(3), 607-620.
[http://dx.doi.org/10.1109/TCBB.2010.75] [PMID: 20733244]
[18]
Li, M.; Li, D.; Tang, Y.; Wu, F.; Wang, J. CytoCluster: A cytoscape plugin for cluster analysis and visualization of biological networks. Int. J. Mol. Sci., 2017, 18(9), 1880.
[http://dx.doi.org/10.3390/ijms18091880] [PMID: 28858211]
[19]
Maere, S.; Heymans, K.; Kuiper, M. BiNGO: A Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics, 2005, 21(16), 3448-3449.
[http://dx.doi.org/10.1093/bioinformatics/bti551] [PMID: 15972284]
[20]
Chen, E.Y.; Tan, C.M.; Kou, Y.; Duan, Q.; Wang, Z.; Meirelles, G.V.; Clark, N.R.; Ma’ayan, A. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics, 2013, 14(1), 128.
[http://dx.doi.org/10.1186/1471-2105-14-128] [PMID: 23586463]
[21]
Bengio, Y.; Ducharme, R.; Vincent, P. A neural probabilistic language model. Adv. Neural Inf. Process. Syst., 2000, 13.
[22]
Stamatoyannopoulos, G. Control of globin gene expression during development and erythroid differentiation. Exp. Hematol., 2005, 33(3), 259-271.
[http://dx.doi.org/10.1016/j.exphem.2004.11.007] [PMID: 15730849]
[23]
Pace, B.S.; Liu, L.; Li, B.; Makala, L.H. Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease. Exp. Biol. Med. (Maywood), 2015, 240(8), 1050-1064.
[http://dx.doi.org/10.1177/1535370215596859] [PMID: 26283707]
[24]
Marinkovic, D.; Zhang, X.; Yalcin, S.; Luciano, J.P.; Brugnara, C.; Huber, T.; Ghaffari, S. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J. Clin. Invest., 2007, 117(8), 2133-2144.
[http://dx.doi.org/10.1172/JCI31807] [PMID: 17671650]
[25]
Fornari, T.A.; Lanaro, C.; Albuquerque, D.M.; Ferreira, R.; Costa, F.F. Featured Article: Modulation of fetal hemoglobin in hereditary persistence of fetal hemoglobin deletion type-2, compared to Sicilian δβ-thalassemia, by Bcl11a and SOX6-targeting microRNAs. Exp. Biol. Med. (Maywood), 2017, 242(3), 267-274.
[http://dx.doi.org/10.1177/1535370216668052] [PMID: 27591578]
[26]
Han, Y.; Huang, L.; Zhou, M.; Tan, X.; Gong, S.; Zhang, Z.; Jin, T.; Fang, X.; Jia, Y.; Huang, S.W. Comparison of transcriptome profiles of nucleated red blood cells in cord blood between preterm and full-term neonates. Hematology, 2022, 27(1), 263-273.
[http://dx.doi.org/10.1080/16078454.2022.2029255] [PMID: 35192776]
[27]
Papasavva, P.L.; Papaioannou, N.Y.; Patsali, P.; Kurita, R.; Nakamura, Y.; Sitarou, M.; Christou, S.; Kleanthous, M.; Lederer, C.W. Distinct miRNA signatures and networks discern fetal from adult erythroid differentiation and primary from immortalized erythroid cells. Int. J. Mol. Sci., 2021, 22(7), 3626.
[http://dx.doi.org/10.3390/ijms22073626] [PMID: 33807258]
[28]
Consortium, E.P. A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol., 2011, 9(4), e1001046.
[http://dx.doi.org/10.1371/journal.pbio.1001046] [PMID: 21526222]
[29]
Rouillard, A.D.; Gundersen, G.W.; Fernandez, N.F.; Wang, Z.; Monteiro, C.D.; McDermott, M.G. The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database, 2016, 2016
[http://dx.doi.org/10.1093/database/baw100]
[30]
Martire, S.; Banaszynski, L.A. The roles of histone variants in fine-tuning chromatin organization and function. Nat. Rev. Mol. Cell Biol., 2020, 21(9), 522-541.
[http://dx.doi.org/10.1038/s41580-020-0262-8] [PMID: 32665685]
[31]
Statello, L.; Guo, C-J.; Chen, L-L.; Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol., 2020, 1-23.
[PMID: 33353982]
[32]
Xu, C.; Shi, L. Long non-coding RNAs during normal erythropoiesis. Blood Sci., 2019, 1(2), 137-140.
[http://dx.doi.org/10.1097/BS9.0000000000000027] [PMID: 35402813]
[33]
Thom, C.S.; Traxler, E.A.; Khandros, E.; Nickas, J.M.; Zhou, O.Y.; Lazarus, J.E.; Silva, A.P.; Prabhu, D.; Yao, Y.; Aribeana, C.; Fuchs, S.Y.; Mackay, J.P.; Holzbaur, E.L.; Weiss, M.J. Trim58 degrades Dynein and regulates terminal erythropoiesis. Dev. Cell, 2014, 30(6), 688-700.
[http://dx.doi.org/10.1016/j.devcel.2014.07.021] [PMID: 25241935]
[34]
Pritlove, D.C.; Gu, M.; Boyd, C.A.; Randeva, H.S.; Vatish, M. Novel placental expression of 2,3-bisphosphoglycerate mutase. Placenta, 2006, 27(8), 924-927.
[http://dx.doi.org/10.1016/j.placenta.2005.08.010] [PMID: 16246416]
[35]
Kondo, A.; Fujiwara, T.; Okitsu, Y.; Fukuhara, N.; Onishi, Y.; Nakamura, Y.; Sawada, K.; Harigae, H. Identification of a novel putative mitochondrial protein FAM210B associated with erythroid differentiation. Int. J. Hematol., 2016, 103(4), 387-395.
[http://dx.doi.org/10.1007/s12185-016-1968-4] [PMID: 26968549]
[36]
Bottardi, S.; Ross, J.; Bourgoin, V.; Fotouhi-Ardakani, N.; Affar, B.; Trudel, M.; Milot, E. Ikaros and GATA-1 combinatorial effect is required for silencing of human γ-globin genes. Mol. Cell. Biol., 2009, 29(6), 1526-1537.
[http://dx.doi.org/10.1128/MCB.01523-08] [PMID: 19114560]
[37]
Khandros, E.; Huang, P.; Peslak, S.A.; Sharma, M.; Abdulmalik, O.; Giardine, B.M.; Zhang, Z.; Keller, C.A.; Hardison, R.C.; Blobel, G.A. Understanding heterogeneity of fetal hemoglobin induction through comparative analysis of F and A erythroblasts. Blood, 2020, 135(22), 1957-1968.
[PMID: 32268371]