Chromatin and Disease Biology Lab

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The eukaryotic interphase chromatin is a highly organized structure. Specific scaffolding proteins form complexes with DNA and play pivotal role in DNA packaging. An important feature of DNA packaging involves folding of the chromatin into loop domains, which are periodically attached to the nuclear matrix through binding to specialized DNA sequences called Matrix Attachment Region or MARs. We study how proteins that specifically bind to MARs regulate genomic DNA organization and nuclear biochemical functions such as transcription, recombination, splicing, repair etc. Past several years our lab has been engaged in understanding the role of nuclear matrix and associated proteins in pathophysiological processes. We have focused on one such novel matrix associated protein SMAR1 that is down regulated in human breast cancer. It acts as a global repressor for many genes including Cyclin D1, IkBa and CK8 by directly recruiting HDAC1-mSin3a dependent repressor complex. Our findings reveal that SMAR1 functions in two different ways to regulate global gene expression. First, it acts as a transcriptional repressor and second, it modulates the transactivation potential of transcriptional co-activators NF-kB and p53. Additionally, NF-kB and p53 regulate various transcription factors involved in oncogenic transformation. These cofactors globally affect various signaling pathways leading to activation of genes that onset the process of tumorigenesis. We are therefore focusing our research work on understanding global gene regulation by SMAR1.