Chromatin and Disease Biology Lab

Topics of Research

Gene regulation and chromatin remodelling in cancer stem cells

Th1-Th2 differentiation of T cells

Regulation of splicing through nuclear matrix binding proteins

Epigenetic regulation during HIV transcription

Molecular mechanisms of DNA damage-repair

Current Projects

Role of SMAR1 in Cancer

Past several years our lab has been engaged in understanding the role of nuclear matrix binding proteins and their association with chromatin modifying complexes in pathophysiological and disease conditions. We have now characterized SMAR1 as a tumor suppressor by virtue of its ability to interact with tumor suppressor p53. We have also shown that SMAR1 delays tumor progression in mouse melanoma model by imposing cell cycle arrest. Additionally, we showed that the tumor suppressor function of SMAR1 resides within the RS domain that interacts with phosphorylated p53 and stabilizes it in the nucleus. Recently we have also shown that Cyclin D1 is a direct transcriptional target of SMAR1 and that SMAR1 is drastically reduced in breast cancer cell lines as well as in various grades of breast carcinoma tissues. SMAR1 regulates the cancer cell proliferation, and metastasis. We also find that chemotherapeutic agents like Doxorubicin induce the expression of SMAR1 in p53 dependent manner. We propose that SMAR1 acts as key regulator of cellular proliferation and metastasis in breast cancer by interplaying between p53 and TGFbpathway.

Role of SMAR1 in modulating cell cycle arrest and apoptosis

How tumor suppressor p53 bifurcates cell cycle arrest and apoptosis and executes these distinct pathways is not clearly understood. We find BAX and PUMA promoters harbor an identical MAR element and are transcriptional targets of SMAR1. Upon mild DNA damage, SMAR1 selectively represses BAX and PUMA through binding to the MAR independently of inducing p53 deacetylation through HDAC1. This generates an anti-apoptotic response leading to cell cycle arrest. Conversely, apoptotic DNA damage results in increased size and number of PML nuclear bodies with consequent sequestration of SMAR1. This facilitates p53 acetylation and restricts SMAR1 binding to BAX and PUMA MAR leading to apoptosis. Thus, our study establishes MAR as a damage responsive cis element and SMAR1-PML crosstalk as a switch that modulates the decision between cell cycle arrest and apoptosis in response to DNA damage. [EMBO,2009]

Regulation of NF-kB mediated transactivation by SMAR1

Regulation of NF-kB activity constitutes an important parameter for maintaining cellular homeostasis. Aberrant NF-kB activity as is seen in advanced grades of many tumors promotes the secretion of various cytokines and chemokines that help tumor cells to escape immunosurveillance and facilitate metastasis and angiogenesis. Therefore, inhibiting NF-kB activity is a major challenge to curb tumor growth. We have identified a distinct mechanism of NF-kB regulation by SMAR1 where we show that chemotherapeutic agents like Doxorubicin inhibit NF-kB mediated transactivation through SMAR1. The preliminary data suggest that SMAR1 can control specific subset of NF-kB target genes which promotes cancer growth, metastasis and angiogenesis.

Regulatory function of SMAR1 during IR induced DNA damage in cancer cells

Preliminary studies from lab suggest that SMAR1 is responsive to various stress stimuli. Therefore identification of stress responsive nature of this protein and delineating the signaling pathway that specifically stimulates the functions of this protein is of paramount importance. Utility of specific post-translational modifiers allows temporal and spatial control over protein relocalization and interactions, and may represent a means for trans-regulatory activation of protein activities. The ability to recognize these specific modifiers also underscores the capacity for signal amplification, a crucial step for the maintenance of genomic stability and tumor prevention. In context with the stress response, we identified a novel ATM phosphorylation site on SMAR1 that mediates an increased association of SMAR1 with Cyclin D1 promoter. The dual effect of SMAR1 i.e. induction of p21 through p53 activation and downregulation of Cyclin D1 by recruitment of corepressor complex causes cell cycle arrest. SMAR1 is induced in response to any genotoxic insult. The studies are ongoing to decipher the roles of SMAR1 upon DNA damage and repair.

SMAR1 Represses HIV-1 LTR mediated transcription through chromatin remodeling

Nuclear Matrix and Matrix Attachment Regions (MARs) have been implicated in the transcriptional regulation of host as well as viral genes but their precise role in HIV-1 transcription remains unclear. Here, we show that >98% of HIV sequences in GenBank contain a consensus MAR element in their 5' LTRs. We further define the role of this MAR in determining the state of viral transcription and show by MAR-binding assays that the transcriptionally silent HIV LTR has a strong propensity to bind to nuclear matrix. The MAR-binding protein SMAR1 aids in tethering LTR-MAR to nuclear matrix thereby enforcing transcriptional silencing. We have also characterized the minimal DNA sequence in the LTR-MAR to which SMAR1 binds and recruits the HDAC1/Sin3A corepressor complex thereby repressing LTR-mediated transcription (Virology, 2010)

Role of SMAR1 in T helper (TH) cell differentiation

The development and function of the T lymphocyte lineage are regulated tightly by signaling pathways that involve lineage-restricted cell surface receptors, intracellular signaling molecules and nuclear transcription factors. Naive T helper cells differentiate into two subsets, TH1 and TH2, each with distinct functions and their respective cytokine profiles. We have earlier shown that SMAR1 down regulates TH1 specific transcription factor T-bet thereby effecting TH1 lineage commitment of T cells. Using SMAR1 transgenic and knockout model we are trying to understand this differentiation process in detail.