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SMAR1 binds to T(C/G) repeat and inhibits tumor progression by regulating miR-371-373 cluster

View Article: PubMed Central - PubMed

ABSTRACT

Chromatin architecture and dynamics are regulated by various histone and non-histone proteins. The matrix attachment region binding proteins (MARBPs) play a central role in chromatin organization and function through numerous regulatory proteins. In the present study, we demonstrate that nuclear matrix protein SMAR1 orchestrates global gene regulation as determined by massively parallel ChIP-sequencing. The study revealed that SMAR1 binds to T(C/G) repeat and targets genes involved in diverse biological pathways. We observe that SMAR1 binds and targets distinctly different genes based on the availability of p53. Our data suggest that SMAR1 binds and regulates one of the imperative microRNA clusters in cancer and metastasis, miR-371-373. It negatively regulates miR-371-373 transcription as confirmed by SMAR1 overexpression and knockdown studies. Further, deletion studies indicate that a ~200 bp region in the miR-371-373 promoter is necessary for SMAR1 binding and transcriptional repression. Recruitment of HDAC1/mSin3A complex by SMAR1, concomitant with alteration of histone marks results in downregulation of the miRNA cluster. The regulation of miR-371-373 by SMAR1 inhibits breast cancer tumorigenesis and metastasis as determined by in vivo experiments. Overall, our study highlights the binding of SMAR1 to T(C/G) repeat and its role in cancer through miR-371-373.

No MeSH data available.


Mapping genome-wide distribution of the nuclear matrix protein SMAR1.(A) Distribution of SMAR1-binding sites within specific gene components as analyzed by the Nearest Downstream Gene (NDG) function of PeakAnalyzer software in HCT116 p53+/+ and HCT116 p53−/−cell lines. (B) The percentage of SMAR1 bound peaks within ±5 kb of Transcription Start Site (TSS) for all gene targets in HCT116 p53+/+ and HCT116 p53−/−cell lines. (C) Comparison of SMAR1 gene targets from HCT116 p53+/+ and HCT116 p53−/− data sets.
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f1: Mapping genome-wide distribution of the nuclear matrix protein SMAR1.(A) Distribution of SMAR1-binding sites within specific gene components as analyzed by the Nearest Downstream Gene (NDG) function of PeakAnalyzer software in HCT116 p53+/+ and HCT116 p53−/−cell lines. (B) The percentage of SMAR1 bound peaks within ±5 kb of Transcription Start Site (TSS) for all gene targets in HCT116 p53+/+ and HCT116 p53−/−cell lines. (C) Comparison of SMAR1 gene targets from HCT116 p53+/+ and HCT116 p53−/− data sets.

Mentions: SMAR1 functions by recruiting co-repressor complex to gene promoter or gene body for regulation of transcription, transcription-coupled splicing, DNA damage repair and other vital cellular functions. Hence, we planned to determine the genome-wide binding pattern of SMAR1 and correlate it with transcription. The analysis suggested that SMAR1 has a diverse binding pattern with respect to different gene components. Approximately, 29% of SMAR1 binding was observed in the promoter regions and regulatory elements (5′UTR and first introns) of the gene in both the data sets. Around 53% of SMAR1 binding was detected within the gene body irrespective of the data set (Fig. 1A).


SMAR1 binds to T(C/G) repeat and inhibits tumor progression by regulating miR-371-373 cluster
Mapping genome-wide distribution of the nuclear matrix protein SMAR1.(A) Distribution of SMAR1-binding sites within specific gene components as analyzed by the Nearest Downstream Gene (NDG) function of PeakAnalyzer software in HCT116 p53+/+ and HCT116 p53−/−cell lines. (B) The percentage of SMAR1 bound peaks within ±5 kb of Transcription Start Site (TSS) for all gene targets in HCT116 p53+/+ and HCT116 p53−/−cell lines. (C) Comparison of SMAR1 gene targets from HCT116 p53+/+ and HCT116 p53−/− data sets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037395&req=5

f1: Mapping genome-wide distribution of the nuclear matrix protein SMAR1.(A) Distribution of SMAR1-binding sites within specific gene components as analyzed by the Nearest Downstream Gene (NDG) function of PeakAnalyzer software in HCT116 p53+/+ and HCT116 p53−/−cell lines. (B) The percentage of SMAR1 bound peaks within ±5 kb of Transcription Start Site (TSS) for all gene targets in HCT116 p53+/+ and HCT116 p53−/−cell lines. (C) Comparison of SMAR1 gene targets from HCT116 p53+/+ and HCT116 p53−/− data sets.
Mentions: SMAR1 functions by recruiting co-repressor complex to gene promoter or gene body for regulation of transcription, transcription-coupled splicing, DNA damage repair and other vital cellular functions. Hence, we planned to determine the genome-wide binding pattern of SMAR1 and correlate it with transcription. The analysis suggested that SMAR1 has a diverse binding pattern with respect to different gene components. Approximately, 29% of SMAR1 binding was observed in the promoter regions and regulatory elements (5′UTR and first introns) of the gene in both the data sets. Around 53% of SMAR1 binding was detected within the gene body irrespective of the data set (Fig. 1A).

View Article: PubMed Central - PubMed

ABSTRACT

Chromatin architecture and dynamics are regulated by various histone and non-histone proteins. The matrix attachment region binding proteins (MARBPs) play a central role in chromatin organization and function through numerous regulatory proteins. In the present study, we demonstrate that nuclear matrix protein SMAR1 orchestrates global gene regulation as determined by massively parallel ChIP-sequencing. The study revealed that SMAR1 binds to T(C/G) repeat and targets genes involved in diverse biological pathways. We observe that SMAR1 binds and targets distinctly different genes based on the availability of p53. Our data suggest that SMAR1 binds and regulates one of the imperative microRNA clusters in cancer and metastasis, miR-371-373. It negatively regulates miR-371-373 transcription as confirmed by SMAR1 overexpression and knockdown studies. Further, deletion studies indicate that a ~200 bp region in the miR-371-373 promoter is necessary for SMAR1 binding and transcriptional repression. Recruitment of HDAC1/mSin3A complex by SMAR1, concomitant with alteration of histone marks results in downregulation of the miRNA cluster. The regulation of miR-371-373 by SMAR1 inhibits breast cancer tumorigenesis and metastasis as determined by in vivo experiments. Overall, our study highlights the binding of SMAR1 to T(C/G) repeat and its role in cancer through miR-371-373.

No MeSH data available.