Alternative RNA splicing in stem cells and cancer stem cells: Importance of transcript-based expression analysis

doi:10.4252/wjsc.v13.i10.1394

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World Journal of Stem Cells

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World J Stem Cells. Oct 26, 2021; 13(10): 1394-1416
Published online Oct 26, 2021. doi: 10.4252/wjsc.v13.i10.1394

Table 1 Genes that undergo splicing events in stem cells and stem-like cancer cells

Type	Gene	Ensembl ID	Alternative RNA splice variants	Activities	Ref.
Non-cancerous stem cell	IGF1	ENSG00000017427	IGF1Ec, IGF1 Ea	IGF-IEc enhances proliferation and represses muscle progenitors differentiation, IGF-IEa activates anabolic pathways	[99]
	POU5F1 (OCT4)	ENSG00000204531	OCT4A, OCT4B, OCT4B1	Play roles in pluripotency and self-renewal of embryonic stem cells	[38]
	RBM4, RBM14, CoAA	ENSG00000173933	CoAZ, ncCoAZ	Influence co-transcriptional splicing	[100]
	DNMT3B	ENSG00000088305	DNMT3B3, DNMT3B3∆5	DNMT3B3∆5 expressed in ESCs and functionally distinct from DNMT3B3	[101]
	VEGFA	ENSG00000112715	VEGF120, VEGF164, VEGF188	All promote MSC proliferation; some enhance paracrine signaling, osteogenic, or endothelial differentiation	[102]
	FGF4	ENSG00000075388	FGF4, FGF4si	FGF4 is important to stem cell maintenance, while FGFsi antagonizes some of FGF4’s activity	[37]
	PKCd	ENSG00000163932	PKCdI, PKCdII	PKCdI is caspasecleavable and PKCdII is caspase in-cleavable	[103]
	POU2F2 (OCT2)	ENSG00000028277	OCT2.2, OCT2.4	Oct2.2 is sufficient to induce neural differentiation in mouse ESCs, Oct2.4 is able to block neural differentiation	[104]
	RMB14, CoAA	ENSG00000239306	CoAA, CoAM	CoAA is downregulated in favor of CoAM during early embryonic development	[105]
	RUNX1	ENSG00000159216	RUNX1a	Increases the capacity of the HSC pool	[41]
	Qki	ENSG00000112531	Qki5	Regulates neural stem cell function	[45]
	PTB	ENSG00000117569	nPTB (PTBP2) with exon 10	Transition of stem cell to neuron cells	[46]
	FOXP1	ENSG00000114861	FOXP1-ES	Promotes the maintenance of ESC pluripotency and contributes to efficient reprogramming of somatic cells into induced pluripotent stem cells	[35]
Cancer stem cell	NUMB	ENSG00000133961	NUMB exon skipping by EMT	Affect the balance between stem-like and non-stem cancer cells	[67]
	KRAS	ENSG00000133703	KRAS4A	Enriched in the cancer stem cell population and helps to modulate the metabolic requirements and stress responses associated with the cancer stem-progenitor cell transition	[70]
	HER2	ENSG00000141736	D16her2	Role in the regulation of the BC stem cells (BCSCs) activity through its functional interaction with the NOTCH family members	[72]
	CD44	ENSG00000026508	CD44s	CD44s isoforms in cancer cells induces stem-like features	[79]
	CD44	ENSG00000026508	CD44v	Promote CSC activities and protecting CSCs from ROS-induced stress	[86]
	α6β1 integrin (ITGA5, VLA-6, CD49f/CD29)	ENSG00000091409	α6Bβ1 integrin	Promotes the function of breast CSCs and tumor initiation	[89]
	FLNB	ENSG00000136068	FLNB exon 30 skipping	Associated with EMT gene signatures in basal-like breast cancer/ establishing the mesenchymal and stem-like cell state in breast cancers	[75]
	DCLK1	ENSG00000133083	DCLK1-long isoforms (Isoforms 2 and 4)	Promotes expression of RCC stem cell markers and increases self-renewal activity	[98]
	POU5F1 (OCT4)	ENSG00000204531	OCT4A	Promotes stemness properties in embryonal carcinoma cells	[38]
	ALDH1	ENSG00000165092	ALDH1A1	Promotes tumorigenesis, mortality, and self-renewal activity in RCC	[98]

IGF-1: Insulin like growth factor 1; POU5F1: POU domain proteins; OCT4: Octamer-binding transcription factor 4; RMB: RNA binding motif protein; DNMT3B: DNA methyltransferase 3 beta; VEGFA: Vascular endothelial growth factor A; FGF4: Fibroblast growth factor 4; PKCd: Protein kinase C delta; RUNX1: RUNX family transcription factor 1; Qki: Isoforms of Quaking; PTB: Polypyrimidine tract binding; FOXP1: Forkhead box p1; NUMB: NUMB endocytic adaptor protein; KRAS: Kirsten rat sarcoma viral oncogene homolog; HER: Erb-B2 receptor tyrosine kinase; CD: Cluster of differentiation; ITGA5: Integrin subunit alpha 5; FLNB: Filamin B; DCLK1: Doublecortin-like kinase 1; ALDH1: Aldehyde dehydrogenase 1.

Table 2 Alternative splicing analysis tools based on isoform-based method and count-based method (including the exon- and event-based approaches)

Tools	Human/ plants/ animals	Types of detecting splices	Type of tool	Year of publish	Ref.	Citation
Isoform-based method
Cuffdiff2	All	-	Linux	2012	[109]	9550
HMMSplicer	All	-	Linux	2010	[110]	79
PennDiff	All	-	Linux	2018	[111]	9
rSeqDiff	All	-	R	2013	[112]	29
DiffSplice	All	-	Windows/Linux	2013	[113]	141
NSMAP	All	-	MatLab package	2011	[114]	46
MISO	All	SE / A3SS / A5SS / MXE / TandemUTR / RI / AF / AL	Linux	2010	[115]	1166
Exon-based method
TopHaT	All	-	Linux	2009	[116]	11026
DEXSeq	All	-	R	2012	[117]	1091
edgeR	All	-	R	2010	[118]	19012
JunctionSeq	All	-	R	2016	[119]	81
limma	All	-	R	2015	[120]	11033
rSeqNP	All	-	R	2015	[121]	10
Event-based method
MAJIQ	All	SE / A5SS / A3SS	Linux	2016	[122]	171
rMATS	All	SE / A5SS / A3SS / RI / MXE	Linux	2014	[123]	746
SUPPA	All	SE / A5SS / A3SS / RI / MXE / AF / AL	Linux	2015	[124]	134
SUPPA2	All	SE / A5SS / A3SS / RI / MXE / AF / AL	Linux	2018	[125]	-
ASGAL	All	SE / A5SS / A3SS / RI	Linux	2018	[126]	12
Astalavista version 3.0	All	SE / A5SS / A3SS / RI	Linux	2012	[127]	62
LeafCutter	All	SE / A5SS / A3SS	Linux	2018	[128]	200
SpliceGrapher	All	SE / A5SS / A3SS / RI	Linux	2012	[129]	132
KisSplice	All	SNPs, indels and AS events (SE / A5SS / A3SS / RI )	Linux	2012	[130]	-
Alt Event Finder	All	SE	Linux	2012	[131]	24
Matt	All	SE / A5SS / A3SS / RI	Linux	2018	[132]	14
ALEXA-seq	All	SE / A5SS / A3SS / RI	Linux	2010	[133]	340
Outrigger	All	SE / A5SS / A3SS / RI	Linux	2016	[134]	86
ASDT	All	SE / A5SS / A3SS / RI	Perl	2018	[135]	5
SplicePie	All	SE / RI	R	2015	[136]	17
VAST-TOOLS	All	SE / A5SS / A3SS / RI	R	2017	[137]	118
spliceR	All	SE / A5SS / A3SS / RI / AF/AL	R	2014	[138]	80
Pro-Splicer	Human	SE / A5SS / A3SS	Website (http://prosplicer.mbc.nctu.edu.tw/)	2003	[139]	50
ASPicDB	Human	SE / A5SS / A3SS / RI / AF/AL	Website (http://srv00.recas.ba.infn.it/ASPicDB/)	2006	[140]	33
H-DBAS	Human	SE / A5SS / A3SS / RI / AF/AL	Website (http://www.h-invitational.jp/h-dbas/)	2007	[141]	56
ASIP	Plant	SE / A5SS / A3SS / RI	Website (http://www.plantgdb.org/ASIP/)	2006	[142]	535
ASG	Human	SE / A5SS / A3SS / RI	Website (https://brcwebportal.cos.ncsu.edu/asg/)	2004	[143]	116
VastDB	vertebrate	SE / A5SS / A3SS / RI	Website (https://vastdb.crg.eu/wiki/Main_Page)	2017	[137]	118
Astalavista	Human/ Animals	SE / A5SS / A3SS / RI	Website (http://astalavista.sammeth.net/)	2007	[144]	205
SpliceDitector	Plant/ Human	SE / A5SS / A3SS / RI	Windows	2018	[11]	1
dSpliceType	All	SE / A5SS / A3SS / RI / MXE	Windows/ Linux	2015	[145]	4
AltAnalyze	All	SE / A5SS / A3SS / RI / MXE	Windows/ Linux	2010	[146]	253

SE: Skipped exon; A3SS: Alternative acceptor site; A5SS: Alternative donor site; RI: Retained intron; MXE: Mutually exclusive exons; AF/AL: Alternative first/last exons.

Citation: Ebrahimie E, Rahimirad S, Tahsili M, Mohammadi-Dehcheshmeh M. Alternative RNA splicing in stem cells and cancer stem cells: Importance of transcript-based expression analysis. World J Stem Cells 2021; 13(10): 1394-1416
URL: https://www.wjgnet.com/1948-0210/full/v13/i10/1394.htm
DOI: https://dx.doi.org/10.4252/wjsc.v13.i10.1394