Limits...
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.

Show MeSH

Related in: MedlinePlus

Gene network analysis shows that the genes regulated by Mta1 in the presence of P53 are involved in the networks associated with antimicrobial and inflammatory responses (statistically most significant network).When compared with the wild type MEFs, the genes that were up regulated in Mta1 knockout MEFs are shown in red and the down regulated genes are shown in green. The network with the highest score from the IPA analysis was considered to be the most significant network and majority of the genes that were found in this network were up-regulated.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3045407&req=5

pone-0017135-g009: Gene network analysis shows that the genes regulated by Mta1 in the presence of P53 are involved in the networks associated with antimicrobial and inflammatory responses (statistically most significant network).When compared with the wild type MEFs, the genes that were up regulated in Mta1 knockout MEFs are shown in red and the down regulated genes are shown in green. The network with the highest score from the IPA analysis was considered to be the most significant network and majority of the genes that were found in this network were up-regulated.

Mentions: The gene ontology analysis again highlights the influence of P53 on Mta1 function. If P53 is present, the targets regulated by Mta1 play no remarkable role in the molecular functions such as catalytic activity or binding where as in the absence of P53 about 39% of genes regulated by Mta1 are involved in molecular functions, clearly indicating the influence of P53 on Mta1 gene regulation. Further extensive comparative analysis of all the data using IPA and networks reveals two distinct functional themes. In the presence of P53, the genes regulated by Mta1 are mainly involved in the inflammatory response cancer and cellular movement. Whereas, in the absence of P53 the genes regulated are predominantly related to cancer signaling reflecting the significance of Mta1 in cancer. In agreement to the above mentioned observations, the top networks and pathways regulated by Mta1 in the presence of P53 appear to be antimicrobial response, inflammatory response and carbohydrate metabolism (Figure 9). For instance, most of the genes regulated by Mta1 revolve around major complexes such as IRF7 (Interferon regulatory factor-7), which has been shown to play important role in the transcriptional activation of virus inducible cellular genes. In addition, as a part of innate antiviral immunity, the induction of systemic IFN takes place through IRF7 [42]. Another gene, Immunity-related GTPases (IRG) that play an important role in defense against intracellular pathogens and NFĸB complex which has been well ascertained to be regulated by Mta1 were also found in the network. In agreement with our data recent studies suggest MTA1 regulating its target genes either by acting as a corepressor [18], [19] or as transcriptional coactivator [20], [21] via interacting with RNA polymerase II. Together, these findings raise the possibility that Mta1 may play a significant role in protecting regulation of innate immune response by directly modulating several pathways including NF-κB signaling [43]. Our data further supports this notion and emphasizes the role of Mta1 in inflammation.


Gene profiling of MTA1 identifies novel gene targets and functions.

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

Gene network analysis shows that the genes regulated by Mta1 in the presence of P53 are involved in the networks associated with antimicrobial and inflammatory responses (statistically most significant network).When compared with the wild type MEFs, the genes that were up regulated in Mta1 knockout MEFs are shown in red and the down regulated genes are shown in green. The network with the highest score from the IPA analysis was considered to be the most significant network and majority of the genes that were found in this network were up-regulated.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017135-g009: Gene network analysis shows that the genes regulated by Mta1 in the presence of P53 are involved in the networks associated with antimicrobial and inflammatory responses (statistically most significant network).When compared with the wild type MEFs, the genes that were up regulated in Mta1 knockout MEFs are shown in red and the down regulated genes are shown in green. The network with the highest score from the IPA analysis was considered to be the most significant network and majority of the genes that were found in this network were up-regulated.
Mentions: The gene ontology analysis again highlights the influence of P53 on Mta1 function. If P53 is present, the targets regulated by Mta1 play no remarkable role in the molecular functions such as catalytic activity or binding where as in the absence of P53 about 39% of genes regulated by Mta1 are involved in molecular functions, clearly indicating the influence of P53 on Mta1 gene regulation. Further extensive comparative analysis of all the data using IPA and networks reveals two distinct functional themes. In the presence of P53, the genes regulated by Mta1 are mainly involved in the inflammatory response cancer and cellular movement. Whereas, in the absence of P53 the genes regulated are predominantly related to cancer signaling reflecting the significance of Mta1 in cancer. In agreement to the above mentioned observations, the top networks and pathways regulated by Mta1 in the presence of P53 appear to be antimicrobial response, inflammatory response and carbohydrate metabolism (Figure 9). For instance, most of the genes regulated by Mta1 revolve around major complexes such as IRF7 (Interferon regulatory factor-7), which has been shown to play important role in the transcriptional activation of virus inducible cellular genes. In addition, as a part of innate antiviral immunity, the induction of systemic IFN takes place through IRF7 [42]. Another gene, Immunity-related GTPases (IRG) that play an important role in defense against intracellular pathogens and NFĸB complex which has been well ascertained to be regulated by Mta1 were also found in the network. In agreement with our data recent studies suggest MTA1 regulating its target genes either by acting as a corepressor [18], [19] or as transcriptional coactivator [20], [21] via interacting with RNA polymerase II. Together, these findings raise the possibility that Mta1 may play a significant role in protecting regulation of innate immune response by directly modulating several pathways including NF-κB signaling [43]. Our data further supports this notion and emphasizes the role of Mta1 in inflammation.

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