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Gene profiling of MTA1 identifies novel gene targets and functions.

Ghanta KS, Li DQ, Eswaran J, Kumar R - PLoS ONE (2011)

Bottom Line: Metastasis-associated protein 1 (MTA1), a master dual co-regulatory protein is found to be an integral part of NuRD (Nucleosome Remodeling and Histone Deacetylation) complex, which has indispensable transcriptional regulatory functions via histone deacetylation and chromatin remodeling.Emerging literature establishes MTA1 to be a valid DNA-damage responsive protein with a significant role in maintaining the optimum DNA-repair activity in mammalian cells exposed to genotoxic stress.Thus, the presented data emphasizes the known functions of Mta1 and serves as a rich resource which could help us identify novel Mta1 functions.

View Article: PubMed Central - PubMed

Affiliation: McCormick Genomic and Proteomic Center, The George Washington University Medical Center, Washington, D.C., United States of America.

ABSTRACT

Background: Metastasis-associated protein 1 (MTA1), a master dual co-regulatory protein is found to be an integral part of NuRD (Nucleosome Remodeling and Histone Deacetylation) complex, which has indispensable transcriptional regulatory functions via histone deacetylation and chromatin remodeling. Emerging literature establishes MTA1 to be a valid DNA-damage responsive protein with a significant role in maintaining the optimum DNA-repair activity in mammalian cells exposed to genotoxic stress. This DNA-damage responsive function of MTA1 was reported to be a P53-dependent and independent function. Here, we investigate the influence of P53 on gene regulation function of Mta1 to identify novel gene targets and functions of Mta1.

Methods: Gene expression analysis was performed on five different mouse embryonic fibroblasts (MEFs) samples (i) the Mta1 wild type, (ii) Mta1 knock out (iii) Mta1 knock out in which Mta1 was reintroduced (iv) P53 knock out (v) P53 knock out in which Mta1 was over expressed using Affymetrix Mouse Exon 1.0 ST arrays. Further Hierarchical Clustering, Gene Ontology analysis with GO terms satisfying corrected p-value<0.1, and the Ingenuity Pathway Analysis were performed. Finally, RT-qPCR was carried out on selective candidate genes.

Significance/conclusion: This study represents a complete genome wide screen for possible target genes of a coregulator, Mta1. The comparative gene profiling of Mta1 wild type, Mta1 knockout and Mta1 re-expression in the Mta1 knockout conditions define "bona fide" Mta1 target genes. Further extensive analyses of the data highlights the influence of P53 on Mta1 gene regulation. In the presence of P53 majority of the genes regulated by Mta1 are related to inflammatory and anti-microbial responses whereas in the absence of P53 the predominant target genes are involved in cancer signaling. Thus, the presented data emphasizes the known functions of Mta1 and serves as a rich resource which could help us identify novel Mta1 functions.

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Gene Ontology (GO) analysis of was performed using Gene Spring GX 10.0.2 (Agilent technologies Inc and Strand Life Sciences Pvt Ltd).With the gene set comparisons that were described in the figure 3A GO analysis was performed. Pie chart A shows the statistically significant (P<0.1) differentially regulated genes between wild type and Mta1-KO samples matching with three broad GO terms (Cellular components, Biological process and Molecular Function), Pie chart B (Mta1-KO and Mta1-KO/Mta1) shows the GO terms matching with the differentially regulated genes in this comparison. Pie chart C and pie chart D show the same for bona fide Mta1 regulated genes in the presence of P53 (126) and P53-KO vs. P53-KO/Mta1 (genes regulated by Mta1 in the absence of P53,266) respectively.
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pone-0017135-g004: Gene Ontology (GO) analysis of was performed using Gene Spring GX 10.0.2 (Agilent technologies Inc and Strand Life Sciences Pvt Ltd).With the gene set comparisons that were described in the figure 3A GO analysis was performed. Pie chart A shows the statistically significant (P<0.1) differentially regulated genes between wild type and Mta1-KO samples matching with three broad GO terms (Cellular components, Biological process and Molecular Function), Pie chart B (Mta1-KO and Mta1-KO/Mta1) shows the GO terms matching with the differentially regulated genes in this comparison. Pie chart C and pie chart D show the same for bona fide Mta1 regulated genes in the presence of P53 (126) and P53-KO vs. P53-KO/Mta1 (genes regulated by Mta1 in the absence of P53,266) respectively.

Mentions: To further investigate the functions of the genes regulated by Mta1, we performed Gene Ontology (GO) analysis on all the sets of genes that are regulated by Mta1 with/without P53 background with a p-value cutoff set to 0.1. The possible functions of the gene sets were broadly classified, in GO program, into three categories namely i) Cellular Component ii) Molecular Function and iii) Biological Process. We found that the 40.23% of the differentially regulated genes in the comparison of WT vs. Mta1-KO, with p-value: 0.1617 related to molecular function, followed by 34.97% with p-value 0.148 connected to Cellular Component and 24.79% of the genes with p-value 0.0944 were associated with the biological process (Figure 4A). In contrast to the above, when Mta1-KO and Mta1-KO with reintroduced Mta1 were compared there were no genes that match the GO terms in the Molecular functioning, whereas majority of them (77.78%, p-value: 0.6994) were related to the cellular component (Figure 4B). With the corrected p-value cut off 0.1 and in the presence of P53, Mta1 doesn't regulate any genes responsible for molecular functioning. The majority of the genes (78.12%) are associated with Cellular Component and 21.88% are associated to Biological Process (Figure 4C). In contrast to the above, in. the absence of P53, 49.8% (p-value: 0.1212) differentially expressed genes were linked to the Cellular Component, 30.61% (p-value: 0.1777) to Molecular Function and 19.59% (p-value: 0.1253) related to Biological Process (Figure 4D). Tables with GO terms for all the above mentioned comparisons are shown in Table 5, 6, 7 and 8 respectively. Table 5 and Table 8 are continued as Tables S8 and S9 respectively.


Gene profiling of MTA1 identifies novel gene targets and functions.

Ghanta KS, Li DQ, Eswaran J, Kumar R - PLoS ONE (2011)

Gene Ontology (GO) analysis of was performed using Gene Spring GX 10.0.2 (Agilent technologies Inc and Strand Life Sciences Pvt Ltd).With the gene set comparisons that were described in the figure 3A GO analysis was performed. Pie chart A shows the statistically significant (P<0.1) differentially regulated genes between wild type and Mta1-KO samples matching with three broad GO terms (Cellular components, Biological process and Molecular Function), Pie chart B (Mta1-KO and Mta1-KO/Mta1) shows the GO terms matching with the differentially regulated genes in this comparison. Pie chart C and pie chart D show the same for bona fide Mta1 regulated genes in the presence of P53 (126) and P53-KO vs. P53-KO/Mta1 (genes regulated by Mta1 in the absence of P53,266) respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045407&req=5

pone-0017135-g004: Gene Ontology (GO) analysis of was performed using Gene Spring GX 10.0.2 (Agilent technologies Inc and Strand Life Sciences Pvt Ltd).With the gene set comparisons that were described in the figure 3A GO analysis was performed. Pie chart A shows the statistically significant (P<0.1) differentially regulated genes between wild type and Mta1-KO samples matching with three broad GO terms (Cellular components, Biological process and Molecular Function), Pie chart B (Mta1-KO and Mta1-KO/Mta1) shows the GO terms matching with the differentially regulated genes in this comparison. Pie chart C and pie chart D show the same for bona fide Mta1 regulated genes in the presence of P53 (126) and P53-KO vs. P53-KO/Mta1 (genes regulated by Mta1 in the absence of P53,266) respectively.
Mentions: To further investigate the functions of the genes regulated by Mta1, we performed Gene Ontology (GO) analysis on all the sets of genes that are regulated by Mta1 with/without P53 background with a p-value cutoff set to 0.1. The possible functions of the gene sets were broadly classified, in GO program, into three categories namely i) Cellular Component ii) Molecular Function and iii) Biological Process. We found that the 40.23% of the differentially regulated genes in the comparison of WT vs. Mta1-KO, with p-value: 0.1617 related to molecular function, followed by 34.97% with p-value 0.148 connected to Cellular Component and 24.79% of the genes with p-value 0.0944 were associated with the biological process (Figure 4A). In contrast to the above, when Mta1-KO and Mta1-KO with reintroduced Mta1 were compared there were no genes that match the GO terms in the Molecular functioning, whereas majority of them (77.78%, p-value: 0.6994) were related to the cellular component (Figure 4B). With the corrected p-value cut off 0.1 and in the presence of P53, Mta1 doesn't regulate any genes responsible for molecular functioning. The majority of the genes (78.12%) are associated with Cellular Component and 21.88% are associated to Biological Process (Figure 4C). In contrast to the above, in. the absence of P53, 49.8% (p-value: 0.1212) differentially expressed genes were linked to the Cellular Component, 30.61% (p-value: 0.1777) to Molecular Function and 19.59% (p-value: 0.1253) related to Biological Process (Figure 4D). Tables with GO terms for all the above mentioned comparisons are shown in Table 5, 6, 7 and 8 respectively. Table 5 and Table 8 are continued as Tables S8 and S9 respectively.

Bottom Line: Metastasis-associated protein 1 (MTA1), a master dual co-regulatory protein is found to be an integral part of NuRD (Nucleosome Remodeling and Histone Deacetylation) complex, which has indispensable transcriptional regulatory functions via histone deacetylation and chromatin remodeling.Emerging literature establishes MTA1 to be a valid DNA-damage responsive protein with a significant role in maintaining the optimum DNA-repair activity in mammalian cells exposed to genotoxic stress.Thus, the presented data emphasizes the known functions of Mta1 and serves as a rich resource which could help us identify novel Mta1 functions.

View Article: PubMed Central - PubMed

Affiliation: McCormick Genomic and Proteomic Center, The George Washington University Medical Center, Washington, D.C., United States of America.

ABSTRACT

Background: Metastasis-associated protein 1 (MTA1), a master dual co-regulatory protein is found to be an integral part of NuRD (Nucleosome Remodeling and Histone Deacetylation) complex, which has indispensable transcriptional regulatory functions via histone deacetylation and chromatin remodeling. Emerging literature establishes MTA1 to be a valid DNA-damage responsive protein with a significant role in maintaining the optimum DNA-repair activity in mammalian cells exposed to genotoxic stress. This DNA-damage responsive function of MTA1 was reported to be a P53-dependent and independent function. Here, we investigate the influence of P53 on gene regulation function of Mta1 to identify novel gene targets and functions of Mta1.

Methods: Gene expression analysis was performed on five different mouse embryonic fibroblasts (MEFs) samples (i) the Mta1 wild type, (ii) Mta1 knock out (iii) Mta1 knock out in which Mta1 was reintroduced (iv) P53 knock out (v) P53 knock out in which Mta1 was over expressed using Affymetrix Mouse Exon 1.0 ST arrays. Further Hierarchical Clustering, Gene Ontology analysis with GO terms satisfying corrected p-value<0.1, and the Ingenuity Pathway Analysis were performed. Finally, RT-qPCR was carried out on selective candidate genes.

Significance/conclusion: This study represents a complete genome wide screen for possible target genes of a coregulator, Mta1. The comparative gene profiling of Mta1 wild type, Mta1 knockout and Mta1 re-expression in the Mta1 knockout conditions define "bona fide" Mta1 target genes. Further extensive analyses of the data highlights the influence of P53 on Mta1 gene regulation. In the presence of P53 majority of the genes regulated by Mta1 are related to inflammatory and anti-microbial responses whereas in the absence of P53 the predominant target genes are involved in cancer signaling. Thus, the presented data emphasizes the known functions of Mta1 and serves as a rich resource which could help us identify novel Mta1 functions.

Show MeSH
Related in: MedlinePlus