Abstract
MESH1 is the metazoan homolog of bacterial SpoT, the main phosphatase that dephosphorylates and degrades (p)ppGpp, the alarmone involved in the bacterial stringent response. The functional role of MESH1 in human cells is unknown. To define the global transcriptional response to MESH1 knockdown, we employed microarrays to perform transcriptome analysis of H1975 when the MESH1 was knocked down using three independent siRNAs targeting MESH1. The changes of each gene were derived by zero-transformation, followed by filtering to derive the genes affected by MESH1 knockdown. These datasets showed the transcriptional features of the mammalian stringent response and identified a prominent TAZ repression. Thus, we performed a second experiment to determine the contribution of TAZ repression to the transcriptional response of MESH1 knockdown by comparing the effects of MESH1-knockdown gene signatures in H1975 cells transduced with control or constitutive active TAZ (TAZS89A). The transcriptional response of these two cells to MESH1 was derived by zero transformation, followed by the effects of TAZ restoration to define the contribution of TAZ repression to the transcriptome features of human stringent response. The transcriptome data will be useful for the mechanistic understanding of the functional role of MESH1 in human cancer cells.
Keywords: MESH1, Stringent response, SpoT, Ferroptosis, TAZ, Proliferation arrest, Stress response
Specifications Table
| Subject | Biological sciences Omics: Transcriptomic |
| Specific subject area | Study the function of human MESH1, a metazoan homolog of SpoT [1], a bacterial protein involved in regulating the level of (p)ppGpp and bacterial stringent responses. The transcriptional response to MESH1 shows significant similarity with the bacterial stringent response and potential evolutionary conservation [2]. |
| Type of data | Table |
| How the data were acquired | In the first experiment, MESH1 was knocked down in H1975 cells by control or three MESH1-targeting siRNAs in triplicates [3,4]. Total RNAs were collected, and their quality was assessed with the Agilent BioAnalyzer. 200 ng RNA was used to generate cDNA using the Ambion MessageAmp kit and interrogated with an Affymetrix U133A GeneChip. The microarray data was normalized by the RMA, and zero transformed to the negative control (siNT) as before [5,6]. The transcriptional responses to MESH1 knockdown (Table 1) are based on the filtering criteria of at least seven observations with absolute log2 values >0.47. GSEA (Gene Set Enrichment Analysis) revealed a depletion of multiple cell cycle and proliferated pathways upon MESH1 knockdown. MESH1 knockdown also reduced the expression of RRM1 (ribonucleotide reductase M1) and RRM2, subunits of ribonucleotide reductase (RNR) responsible for dNTP synthesis. In the second experiment, the contribution of TAZ repression to the transcriptome response was defined by comparing MESH1-knockdown gene signatures between the control and TAZS89A-transfected H1975. TAZ restoration reversed the changes of at least 1.5 fold of the MESH1-affected genes (Table 2). |
| Data format | Analyzed Filtered |
| Description of data collection | Total RNAs were isolated by RNeasy Mini Kit (Qiagen, #74104) and used to generate cDNA using the Ambion MessageAmp Premier RNA Amplification. The labeled cDNA samples were interrogated with an Affymetrix U133A GeneChip. The data were normalized by the RMA and the expression value of each genes in the siMESH1 groups was compared with the expression value of the same genes in the negative control (siNT) to derive the changes in gene expression. Data were then filtered with Cluster 3.0 and clustered by the genes and shown in tables. |
| Data source location | • Duke School of Medicine • Durham, North Carolina • USA |
| Data accessibility | Name: NCBI Gene Expression Omnibus https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE135358 The transcriptional response to MESH1 silencing https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE135346 TAZ overexpression partially rescued the transcriptomic reprogramming triggered by MESH1 silencing Mendeley Data: Chi, Jen-Tsan Ashley (2022), “Genes whose expression are affected by MESH1 knockdown in H1975”, Mendeley Data, V2, doi:10.17632/hgy8rxmj62.2 |
| Related research article | For a published article: Sun T, Ding CC, Zhang Y, Zhang Y, Lin CC, Wu J, Setayeshpour Y, Coggins S, Shepard C, Macias E, Kim B, Zhou P, Gordân R, Chi JT. MESH1 knockdown triggers proliferation arrest through TAZ repression. Cell Death Dis. 2022 Mar 10;13(3):221. doi:10.1038/s41419-022-04663-6. PMID: 35273140; PMCID: PMC8913805. |
Value of the Data
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•
These data are the first transcriptome studies of the functional role of MESH1 in human cancer cells.
-
•
Transcriptome analysis of mammalian stringent response will enable the cross-kingdom analysis from bacteria [7], Drosophila [1] and human cancer cells [3,4,8].
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•
Ferroptosis is a newly recognized form of cell death with important disease relevance [9]. We have performed forward genetic screens to identified many novel determinants of ferroptosis [10], [11], [12], [13]. MESH1 was identified in a genome-wide RNAi screen [14] and the knockdown of MESH1 robustly protected ferroptosis [4]. In addition, MESH1 knockdown is associated with dramatic proliferation arrest with therapeutic potential. Therefore, the data presented may provide insight into ferroptosis.
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•
The data could be of interest to any investigators interested in the bacterial stringent response and other stress responses in different organisms across evolution.
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•
These data represent a novel stress response of human tumors that has not been described.
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•
The transcriptome data can be useful for another investigator to study the conservation of stress response.
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•
Identify the unexpected association between other biological processes and chemical/genetic perturbations.
1. Objective
While MESH1 was found to regulate ferroptosis by degrading NADPH, its knockdown also robustly reduced the proliferation of cancer cells. To understand the mechanisms underlying such dramatic phenotypes, we performed transcriptome analysis to fully characterize the genes and molecular pathways affected by MESH1 knockdown. Such analysis will also allow us to compare the transcriptional response of mammalian stringent response with what has been published in flies and bacteria. These data highlighted the importance of TAZ mRNA repression as a critical feature of the MESH1 knockdown and mammalian stringent response. Therefore, we performed the second transcriptome experiment in which TAZ is over-expressed as MESH1 was knockdown. These experiments allowed us to dissect the transcriptome changes of MESH1 knockdown into TAZ-dependent vs. TAZ-independent components. The data article adds value to the published articles by highlighting the scientific rationales and experimental designs of these two transcriptome experiments for the academic community.
2. Data Description
To define the transcriptional response to MESH1 knockdown, we knockdown MESH1 in H1975 cells with independent siRNAs and performed transcriptomic analysis [2].
First, the raw data in the GSE135358 were generated by the microarray interrogation of the RNA samples of H1975 transfected with control or three different siRNA targeting MESH1 in triplicate [3,4]. After 48 h of transfection, the total RNAs were collected from these cells and quality was validated using the Agilent BioAnalyzer. 200 ng RNA was used to generate cDNA using the Ambion MessageAmp kit and interrogated with an Affymetrix U133A GeneChip. The microarray data were normalized by the RMA, and zero transformed to the negative control (siNT) as before [5,6].
Table 1 showed the genes whose expression was affected by MESH1 knockdown in H1975 cells. The microarray data were normalized by the RMA, and zero transformed to the negative control (siNT) as before [5,6]. The genes were then filtered based on the filtering criteria of at least seven observations with absolute log2 values >0.47 and cluster of genes affected by MESH1 knockdown were listed in Table 1. The seven was used as filtering criteria to select changes consistent in more than two sample groups. Such analysis revealed a prominent transcriptional repression of TAZ, but not YAP, upon MESH1 knockdown.
Table 1.
List of differentially expressed genes in H1975 upon the knockdown of MESH1 by three independent siRNAs targeting MESH1.
| Gene Symbol |
|---|
| NREP |
| NREP |
| HDAC5 |
| SYT1 |
| CA11 |
| AKR1C3 |
| PCDHA1 /// PCDHA10 /// PCDHA11 /// PCDHA12 /// PCDHA13 /// PCDHA2 /// PCDHA3 /// PCDHA4 /// PCDHA5 /// PCDHA6 /// PCDHA7 /// PCDHA8 /// PCDHA9 /// PCDHAC1 /// PCDHAC2 |
| ZNF467 |
| KLRC3 |
| GSN |
| ARG2 |
| DDAH1 |
| NMNAT2 |
| CDC14B |
| DIP2C |
| DZANK1 |
| RUNDC3A |
| STK19 |
| HIST1H2BC /// HIST1H2BE /// HIST1H2BF /// HIST1H2BG /// HIST1H2BI |
| HIST1H2BE |
| HIST1H2BD |
| HIST1H2BC /// HIST1H2BE /// HIST1H2BF /// HIST1H2BG /// HIST1H2BI |
| IFT22 |
| INPP5A |
| SIK1 |
| CFB |
| ATF3 |
| RHOD |
| KLK6 |
| MGLL |
| UAP1L1 |
| DSP |
| KLHDC3 |
| KLHDC3 |
| GOLGB1 |
| DDAH2 |
| DDAH2 |
| DDAH2 |
| TPM4 |
| KDM2A |
| CCDC176 |
| FLRT2 /// LOC100506718 |
| CCPG1 /// DYX1C1-CCPG1 |
| CCPG1 /// DYX1C1-CCPG1 |
| RRAGD |
| LCAT |
| ZBTB5 |
| CFDP1 |
| IQCJ-SCHIP1 /// SCHIP1 |
| SAT1 |
| SAT1 |
| SAT1 |
| CASP7 |
| UBE2L6 |
| RABAC1 |
| OAZ3 |
| C11orf80 |
| NABP1 |
| ITGB5 |
| PLAG1 |
| CXADR |
| COL18A1 |
| PIM1 |
| MCCC1 |
| OPTN |
| VAMP5 |
| ATP9A |
| HABP4 |
| ZER1 |
| CDC14B |
| HBP1 |
| TBC1D9 |
| UBAP2L |
| AKR1A1 |
| BBS1 |
| CTSB |
| E2F3 |
| EHD1 |
| EHD1 |
| EHD1 |
| DNAJC1 |
| ARID3A |
| CCDC93 |
| CARS |
| RRAGD |
| TMEM43 |
| DYNC1H1 |
| TTC9 |
| CARHSP1 |
| SIGIRR |
| SIGIRR |
| SPCS3 |
| LPIN2 |
| LTBP1 |
| ITGB5 |
| HDAC9 |
| C11orf95 |
| ADCY9 |
| SLC2A3 |
| DNAJB9 |
| CTSB |
| SLC2A3 |
| CTSB |
| EDEM1 |
| SLC2A14 /// SLC2A3 |
| KLF9 |
| AGR2 |
| ZNF83 |
| G3BP2 |
| ZNF267 |
| PHACTR2 |
| ACYP2 /// LOC101927144 |
| PAEP |
| VPS28 |
| CREBL2 |
| DLG5 |
| ANKRA2 |
| KIAA1598 |
| 02-Mar |
| HIST1H1C |
| CDKN1C |
| CDKN1C |
| — |
| CDKN1C |
| CDKN1C |
| AHNAK2 |
| CREBL2 |
| IFT20 |
| FOS |
| KDR |
| KCNJ15 |
| DPYSL3 |
| MTF2 |
| RSL1D1 |
| PHTF2 |
| RSL1D1 |
| HIST1H2BC /// HIST1H2BE /// HIST1H2BF /// HIST1H2BG /// HIST1H2BI |
| ANGPTL4 |
| IL24 |
| OSTM1 |
| MAFF |
| DUSP3 |
| PHACTR2 |
| RGL2 |
| STX4 |
| SPAG7 |
| TUSC3 |
| CTSB |
| CDYL |
| NUPL1 |
| BIK |
| EFTUD1 |
| RAB17 |
| PLEKHA1 |
| KAT2B |
| ZNF702P |
| LY96 |
| CHIC2 |
| MAPK6 |
| TLK2 |
| CBY1 |
| EMC6 |
| CDC37L1 |
| IL6R |
| CREB3 |
| ARL14 |
| MUT |
| JUN |
| HIST1H4H |
| IFT88 |
| HIST1H2AG /// HIST1H2AH /// HIST1H2AI /// HIST1H2AK /// HIST1H2AL /// HIST1H2AM |
| BSPRY |
| HIST1H2BG /// HIST1H2BJ |
| HIST1H2AE |
| BICD2 |
| HIST2H2AA3 /// HIST2H2AA4 |
| HIST2H2AA3 /// HIST2H2AA4 |
| LINC00339 |
| S100A13 |
| PSENEN |
| CCDC53 |
| AHNAK |
| DDX43 |
| C2orf54 |
| MAD2L1 |
| CCT2 |
| MCM6 |
| PLK1 |
| GTSE1 /// TRMU |
| EPB41L2 |
| ACOX2 |
| ACLY |
| ABCE1 |
| EVI2B |
| SRSF1 |
| LHX6 |
| ACLY |
| EOGT |
| PRPS1 |
| KIF14 |
| MIR636 /// SRSF2 |
| RAD54B |
| RFWD3 |
| MDFIC |
| NAA50 |
| MIS18BP1 |
| SLC29A1 |
| STRAP |
| MRTO4 |
| TMPO |
| RAC2 |
| HNRNPH1 |
| H2AFX |
| IL1RL1 |
| TUBGCP3 |
| UBE2D2 |
| ARHGAP22 |
| RAB28 |
| KPNA4 |
| PARN |
| DUSP9 |
| TLE3 |
| FBXO11 |
| NBN |
| HIP1 |
| RGS4 |
| GJA9-MYCBP /// MYCBP |
| HNRNPA2B1 |
| DAZAP1 |
| ARTN |
| ARTN |
| ARTN |
| PPP6R3 |
| RBM8A |
| NHLRC2 |
| WDR77 |
| WWTR1 |
| PRR3 |
| IDH3A |
| PRPF4 |
| NAA15 |
| ARF6 |
| HIPK2 |
| IL1RN |
| C6orf62 |
| STIP1 |
| BCLAF1 |
| BCLAF1 |
| NBN |
| WWTR1 |
| PIGL |
| DHX15 |
| SERBP1 |
| MIR4745 /// PTBP1 |
| SMC4 |
| GPR107 |
| BUB1 |
| ENO1 |
| PRKAR2B |
| CD44 |
| LOC101928747 /// RBMX /// SNORD61 |
| DARS2 |
| CEP152 |
| SRSF11 |
| BCLAF1 |
| TRIM14 |
| TRIM14 |
| MBNL1 |
| TMED2 |
| ARF1 /// MIR3620 |
| TUBB2A /// TUBB2B |
| STC1 |
| STC1 |
| CSNK2A1 |
| LPAR1 |
| RBM12 |
| ZNF586 |
| HNRNPD |
| SORD |
| SORD |
| BASP1 |
| PDHA1 |
| HNRNPD |
| 06-Mar |
| KIAA1462 |
| PRMT3 |
| NT5DC2 |
| PTGES |
| C6orf62 |
| PRKX |
| TIA1 |
| H2AFV |
| H2AFV |
| FAM115A /// LOC100294033 |
| FAM115A /// LOC100294033 |
| ELAVL1 |
| ALDH3A2 |
| ALDH1A3 |
| KRAS |
| ARMC9 |
| ZNF207 |
| GPR125 |
| ADO |
| CYB5B |
| DESI1 |
| LIPG |
| GTPBP8 |
| SDHD |
| LRRC59 |
| MRPL44 |
| GPRC5B |
| SCLY |
| FUBP1 |
| ANKLE2 |
| QRSL1 |
| AMACR /// C1QTNF3-AMACR |
| SPATS2L |
| MALL |
| PSME3 |
| HNRNPUL1 |
| NAP1L1 |
| OPA1 |
| PPP2R1B |
| TRIM14 |
| LRRK1 |
| ACTR3B |
| HNRNPUL1 |
| MAP3K7 |
| ACSL3 |
| ACSL3 |
| SEC23IP |
| ARHGEF26 |
| ALDOC |
| METAP1 |
| POT1 |
| FASTKD2 |
| PUS7 |
| GATC |
| IL18 |
| CALML4 |
| CALML4 |
| TIA1 |
| NAP1L1 |
| RRP15 |
| PEG10 |
| CA2 |
| ARHGAP29 |
| ACTB |
| FCF1 |
| ABLIM1 |
| THEMIS2 |
| U2SURP |
| PAPOLA |
| HHEX |
| METAP2 |
| PTER |
| DLG1 |
| TAF6L |
| FAH |
| EVI2A |
| NETO2 |
| CDK1 |
| CDC25C |
| CDC6 |
| SRSF6 |
| GINS1 |
| FADS1 /// MIR1908 |
| FADS1 /// MIR1908 |
| FADS1 /// MIR1908 |
| CBLL1 |
| NRP1 |
| DKK1 |
| VDAC1 |
| FUS |
| TBCE |
| CKB |
| AASDHPPT |
| HIRA |
| ATP2A2 |
| STARD7 |
| WDR3 |
| MOCOS |
| LRRC40 |
| GEMIN2 |
| AIDA |
| RRM2 |
| RRM1 |
| RRM1 |
Next, to determine the role of TAZ repression in the transcriptional response of MESH1, we produced the raw data in GSE135346. H1975 cells were first transduced by control empty vector or TAZS89A, a constitutive form of TAZ. The cells were then selected by puromycin to select cells with control or TAZS89A-overexpression lentivirus. These cells were then transfected with control or MESH1-targeting siRNAs for 48 h. At this point, the total RNAs were collected from these cells and quality was validated using the Agilent BioAnalyzer. 200 ng RNA was used to generate cDNA using the Ambion MessageAmp kit and interrogated with an Affymetrix U133A GeneChip. The microarray data were normalized by the RMA, and zero transformed to the negative control (siNT). Table 2 showed the list of genes whose expression was affected by MESH1 knockdown, but then reversed upon TAZS89A expression by at least 1.5-fold (Table 2).
Table 2.
List of differentially expressed genes affected by TAZS89A at least 1.5-fold in MESH1-knockdown H1975.
| Gene Symbol |
|---|
| BLNK |
| AKR1C3 |
| CCL5 |
| HOXD1 |
| KIAA0125 |
| VTCN1 |
| CCL5 |
| CHI3L1 |
| CHI3L1 |
| PDE4DIP /// LOC727893 |
| TNFSF10 |
| CLIC2 |
| SP100 |
| C5orf13 |
| MN1 |
| C10orf81 |
| CLEC2B /// CDRT15P |
| HLA-DPA1 |
| NFE2 |
| HLA-DRA |
| NAV3 |
| SOX2 |
| ABCA1 |
| POU2F3 |
| LYPD1 |
| SPP1 |
| VAV3 |
| GNAL |
| GBP1 |
| CTSS |
| PDE4DIP |
| ABCA1 |
| GBP1 |
| ZBTB1 |
| HLA-DMB |
| HLA-DRA |
| TNFSF10 |
| HLA-DMA |
| MSMB |
| BIRC4BP |
| PDE4DIP |
| NAV2 |
| LMO2 |
| TJP3 |
| CASC1 |
| C9orf61 |
| HPGD |
| TJP3 |
| CTSS |
| OAS1 |
| GBP2 |
| MMP13 |
| ABCA12 |
| AGT |
| MPPE1 |
| CYR61 |
| KLHL24 |
| TNFSF10 |
| INDO |
| CYR61 |
| SNAI2 |
| BDKRB2 |
| PDGFD |
| KLRC3 |
| FA2H |
| GRAMD1C |
| HPGD |
| S100P |
| MUC16 |
| CMAH |
| TP73L |
| SLC28A3 |
| IGHA1 |
| MX1 |
| 04-Sep |
| CFB |
| MAF |
| LDB3 |
| HPGD |
| MPPE1 |
| KLHL24 |
| OAS1 |
| IL1R1 |
| AVIL |
| RSAD2 |
| ABAT |
| CEBPD |
| IGHA1 /// IGHA2 |
| RALGPS1 |
| SLC16A4 |
| ADRB1 |
| CTNNA2 |
| SLAMF7 |
| KLF4 |
| ASAH1 |
| PDE4DIP |
| VPS13C |
| GABARAPL1 /// GABARAPL3 |
| KLF4 |
| CTGF |
| RAB15 |
| DSC2 |
| C5orf13 |
| HIST1H4H |
| ISGF3G |
| HIST1H2AM |
| HIST1H2AE |
| MGC17330 |
| MLLT3 |
| TncRNA |
| HERC6 |
| PBXIP1 |
| HIST1H2AG |
| LOC653483 |
| — |
| SLC2A5 |
| SLC12A8 |
| KLF2 |
| C5orf13 |
| MIA3 |
| STK38L |
| LASS4 |
| TXNIP |
| NUPR1 |
| HDAC9 |
| GABARAPL1 |
| PBXIP1 |
| ASAH1 |
| IFI44L |
| GLUL |
| FGFR3 |
| — |
| RELN |
| CDH5 |
| PPAP2A |
3. Experimental Design, Materials and Methods
The primary objective of this experiment was to identify the genes whose expression might be affected by the knockdown of the MESH1 as the transcriptional features of the mammalian stringent response. Furthermore, we will determine the degree to which TAZ restoration can mitigate the transcriptional response to the MESH1 knockdown.
3.1. Cell Lines and Cell Culture
H1975 cell lines were obtained from ATCC and cultured in the standard cell culture conditions with DMEM with 10% FCS, glutamine and penicillin/streptomycin. To mimic the loss of MESH1, we transfected H1975 with control siRNAs and three additional siRNAs that target MESH1 at different regions of MESH1 mRNA. The successful knockdown of the MESH1 were validated by qRT-PCR and Western blots.
3.2. RNA Extraction, Quality Control and Microarray Profiling
Total RNA was extracted from H1975 cells treated with control of MESH1-targeting siRNAs in triplicate using RNeasy Mini Kit (Qiagen, Germany) based on the manufacturer's protocol. Total RNAs were collected with RNeasy Mini Kit (Qiagen, #74104) and assessed with the Agilent BioAnalyzer. RNA quality and quantity were determined using Bioanalyzer (Agilent Corporation, USA) and NanoDrop spectrophotometer (Thermo Fisher Scientific, Wilmington, USA) for concentration cDNAs were generated from 200 ng RNA using the Ambion MessageAmp Premier RNA Amplification (Life Technologies, Grand Island NY, USA) to generate biotin-labeled samples for hybridization. The resulting probes were then hybridized with GeneChip arrays overnight in the Affymetrix hybridization oven at 42 °C. Next, the Affymetrix GeneChip Fluidics Station 450 performs the automated Affymetrix wash and stain protocols. Afterward, The Affymetrix GeneChip Scanner 3000 7G is used to generate the resultant GeneChip array image at the Duke Microarray Facility.
3.3. Data Analysis
The microarray data were normalized by the RMA (Robust Multi-Array) algorithm. and zero transformed to the negative control (siNT), where we compared transcript levels for each gene in siMESH1 groups to the siNT group (n = 3 biologically independent replicates in each siRNA group). Data were then filtered with Cluster 3.0 based on the criteria at least seven observations with absolute log2 values >0.47and then clustered by the genes. The list of genes affected by MESH1 knockdown were shown in Table 1. For the TAZ-affected genes, the genes were selected by affecting at least 1.5-fold by TAZS89A as shown in Table 2.
Ethics Statements
This study does not involve human subjects or samples derived from human materials. It also does not involve vertebrate animals. However, we have used human cancer cell lines from ATCC and other commercial sources, whose use has been approved under the Duke Biosafety Protocol 14-0048-05.
CRediT authorship contribution statement
Tianai Sun: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Chien-Kuang Cornelia Ding: Conceptualization, Methodology, Investigation, Writing – review & editing. Jen-Tsan Chi: Conceptualization, Supervision, Project administration, Funding acquisition, Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Funding: This work was supported by DOD (W81XWH-17-1-0143, W81XWH-15-1-0486, and DOD KC180120) and NIH (R01GM124062, R21-AI149205-01, R21-AG077075).
Data availability
References
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