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.
Highlights
MicroRNAs are endogenous, evolutionarily conserved, small noncoding RNAs that control post-transcriptional gene regulation[7]
We have focused on the role of SMAR1 as a global gene regulator involved in multiple biological pathways, and as a tumor suppressor protein via transcriptional repression of the miR-371-373 cluster
As SMAR1 can alter the function of p53 in response to the severity of DNA damage and differentially drive the cell towards cell cycle arrest or apoptosis[6], its role as a critical transcriptional switch becomes undisputed
Summary
MicroRNAs (miRNAs) are endogenous, evolutionarily conserved, small noncoding RNAs that control post-transcriptional gene regulation[7]. They bind to the 3′UTR of their target mRNAs through an imperfect match, thereby suppressing their translation and stability[8]; reports suggest that miRs can bind to gene promoters enhancing gene transcription[9]. MicroRNA-microarray analysis upon SMAR1 over expression and knockdown in HCT116 p53+/+ cells identified microRNAs essential for erythropoiesis, pluripotency of stem cells, apoptosis, cell cycle and tumorigenesis (Supplementary Fig. S1) One such interesting cluster of miRNAs important in stem cell pluripotency and cancer progression is the miR-371-373 cluster. We have focused on the role of SMAR1 as a global gene regulator involved in multiple biological pathways, and as a tumor suppressor protein via transcriptional repression of the miR-371-373 cluster
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