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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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Ingenuity Pathway Analysis (Ingenuity Systems, Inc) of the genes that were regulated by Mta1 in the presence of P53 was performed.The significance of each function or canonical pathway is determined based upon the p-values determined using Right tailed Fisher's exact test and with threshold less than 0.05. The top 15 possible functions and canonical pathways of the genes regulated by Mta1 in P53 dependent manner are shown. Ratio of number of genes in a given pathway satisfying the cutoff and total number of genes present in that pathway was determined by IPA.
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pone-0017135-g005: Ingenuity Pathway Analysis (Ingenuity Systems, Inc) of the genes that were regulated by Mta1 in the presence of P53 was performed.The significance of each function or canonical pathway is determined based upon the p-values determined using Right tailed Fisher's exact test and with threshold less than 0.05. The top 15 possible functions and canonical pathways of the genes regulated by Mta1 in P53 dependent manner are shown. Ratio of number of genes in a given pathway satisfying the cutoff and total number of genes present in that pathway was determined by IPA.

Mentions: Ingenuity pathways analysis was performed on all the genes that were identified to be regulated by Mta1 with/without P53. With p-value<0.05, Fischer's exact test was applied and we found top 15 significant functions and canonical pathways in which the genes regulated by Mta1 might play a significant role. The most likely functions of the genes regulated by Mta1 in the presence of P53 are Inflammatory Response followed by Cancer and Gastrointestinal Diseases (Figure 5 upper panel). Top 15 canonical pathways of these genes were identified with the p-value<0.05 and threshold value of log (p-value): 0.05. The significant pathways which include LXR/RXR activation, Interferon signaling, Antigen presentation pathway and Activation of IRF by cytosolic pattern Recognition Receptors were shown in Figure 5 (lower panel). From these observations we propose that Mta1 might have critical functional role in orphan nuclear receptor activation, inflammation and infections. Similarly, top 15 plausible functions of the genes regulated by Mta1 in the absence of P53 were identified and shown in Figure 6 (upper panel). The most significant function of the genes was found to be related to ‘Cancer’ followed by ‘Cellular Movement’ and ‘Connective Tissue Disorders’. The top 15 canonical pathways in which the genes might be involved were identified and shown in the Figure 6 (lower panel). The most significant canonical pathway identified is ‘Acute Phase response Signaling’ followed by Colorectal Cancer Metastasis Signaling, Hepatic fibrosis and ‘Bladder Cancer Signaling’. Clearly the genes regulated by Mta1 in the absence of P53 highlight the typical oncogenic character of Mta1 and its possible major role in several cancers and oncogenic signaling pathways.


Gene profiling of MTA1 identifies novel gene targets and functions.

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

Ingenuity Pathway Analysis (Ingenuity Systems, Inc) of the genes that were regulated by Mta1 in the presence of P53 was performed.The significance of each function or canonical pathway is determined based upon the p-values determined using Right tailed Fisher's exact test and with threshold less than 0.05. The top 15 possible functions and canonical pathways of the genes regulated by Mta1 in P53 dependent manner are shown. Ratio of number of genes in a given pathway satisfying the cutoff and total number of genes present in that pathway was determined by IPA.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017135-g005: Ingenuity Pathway Analysis (Ingenuity Systems, Inc) of the genes that were regulated by Mta1 in the presence of P53 was performed.The significance of each function or canonical pathway is determined based upon the p-values determined using Right tailed Fisher's exact test and with threshold less than 0.05. The top 15 possible functions and canonical pathways of the genes regulated by Mta1 in P53 dependent manner are shown. Ratio of number of genes in a given pathway satisfying the cutoff and total number of genes present in that pathway was determined by IPA.
Mentions: Ingenuity pathways analysis was performed on all the genes that were identified to be regulated by Mta1 with/without P53. With p-value<0.05, Fischer's exact test was applied and we found top 15 significant functions and canonical pathways in which the genes regulated by Mta1 might play a significant role. The most likely functions of the genes regulated by Mta1 in the presence of P53 are Inflammatory Response followed by Cancer and Gastrointestinal Diseases (Figure 5 upper panel). Top 15 canonical pathways of these genes were identified with the p-value<0.05 and threshold value of log (p-value): 0.05. The significant pathways which include LXR/RXR activation, Interferon signaling, Antigen presentation pathway and Activation of IRF by cytosolic pattern Recognition Receptors were shown in Figure 5 (lower panel). From these observations we propose that Mta1 might have critical functional role in orphan nuclear receptor activation, inflammation and infections. Similarly, top 15 plausible functions of the genes regulated by Mta1 in the absence of P53 were identified and shown in Figure 6 (upper panel). The most significant function of the genes was found to be related to ‘Cancer’ followed by ‘Cellular Movement’ and ‘Connective Tissue Disorders’. The top 15 canonical pathways in which the genes might be involved were identified and shown in the Figure 6 (lower panel). The most significant canonical pathway identified is ‘Acute Phase response Signaling’ followed by Colorectal Cancer Metastasis Signaling, Hepatic fibrosis and ‘Bladder Cancer Signaling’. Clearly the genes regulated by Mta1 in the absence of P53 highlight the typical oncogenic character of Mta1 and its possible major role in several cancers and oncogenic signaling pathways.

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