Saïd Sif

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Associate Professor

Ph.D. - Boston University
Post Doctoral - Massachusetts General Hospital and Harvard Medical School

Research in my laboratory focuses on understanding how ATP-dependent chromatin remodeling complexes in concert with DNA- and histone-modifying enzymes regulate cell growth and proliferation by changing chromatin structure. More specifically, my group investigates how aberrations in expression and recruitment of chromatin remodelers and epigenetic modifiers contribute to cancer etiology. Recent advances in the field of chromatin have shown that epigenetic modification of chromatin plays a central role in the way cells integrate signals and communicate with their environment. It has also become abundantly clear that various diseases exhibit changes in expression and/or targeting of chromatin-modifying enzymes. Thus, a major challenge in understanding and diagnosing various forms of cancers and diseases that affect metabolic pathways is to identify relevant chromatin changes and to devise tools to reestablish and maintain normal patterns of gene expression in diseased cells.

To address some of these issues, we have established stable cell lines that express either sense or anti-sense cDNAs of various chromatin modifying enzymes, and developed reagents that can allow us to study expression as well as recruitment of epigenetic modifiers to key target genes, such as suppressor of tumorigenecity 7 (ST7), in a wide variety of cancer cells including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). We have also established in the laboratory various platforms and techniques to answer questions relevant to human health. For instance, we have developed a ChIP-on-Chip platform to identify global signatures and gene expression programs using reagents designed to detect chromatin modifiers and epigenetic marks identified in the laboratory. Because most of our research efforts are directed toward finding better diagnostic tools that can be used to accurately characterize clinical outcome before and after treatment with existing and novel drugs, and development of new therapeutic agents that can be used to treat diseases such as cancer, my group currently investigates how expression of protein arginine methyltransferases (PRMTs) is altered in MCL and CLL, and how this imbalance affects histone arginine methylation and impacts other epigenetic marks such as histone lysine methylation and DNA methylation. Furthermore, since histone-modifying enzymes are not sufficient to efficiently alter transcriptional performance, my group also studies mechanisms by which the multi-functional SWI/SNF chromatin remodeling complex, co-repressors, and co-activators integrate transcriptional responses to distinct growth regulatory pathways. Specific target oncogenes and tumor suppressors are examined epigenetically, transcriptionally, and translationally to effectively diagnose the various steps altered in cancer cells and to assess the efficacy of various strategies, designed to restore normal expression of epigenetic modifiers and their targets, in inhibiting cancer cell growth.

Recent Publications:

• Sharma SM, Sif S, Ostrowski MC and Sankar U (2009) "Defective co-activator recruitment in osteoclasts from microphthalmia-oak ridge mutant mice" J Cell Physiol 220(1):230-7.
• Dacwag CS, Bedford MT, Sif S and Imbalzano AN (2009) "Distinct protein arginine methyltransferases promote ATP-dependent chromatin remodeling function at different stages of skeletal muscle differentiation" Mol Cell Biol 29(7):1909-21.
• Wang L, Pal S and Sif S (2008) "Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells" Mol Cell Biol 28(20):6262-77.
• Pal S, Baiocchi RA, Byrd JC, Grever MR, Jacob ST and Sif S (2007) "Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma" EMBO J 26(15):3558-69.
• Pal S and Sif S (2007) "Interplay between chromatin remodelers and protein arginine methyltransferases" J Cell Physiol 213(2):306-15.
• Zhang Y, Sif S and Dewille J (2007) "The mouse C/EBPdelta gene promoter is regulated by STAT3 and Sp1 transcriptional activators, chromatin remodeling and c-Myc repression" J Cell Biochem 102(5):1256-70.
• Sharma SM, Bronisz A, Hu R, Patel K, Mansky KC, Sif S and Ostrowski MC (2007) "MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation" J Biol Chem 282(21):15921-9.
• Dacwag CS, Ohkawa Y, Pal S, Sif S and Imbalzano AN (2007) "The protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates ATP-dependent chromatin remodeling" Mol Cell Biol 27(1):384-94.
• Harikrishnan KN, Pal S, Yarski M, Baker EK, Chow MZ, de Silva MG, Okabe J, Wang L, Jones PL, Sif S and El-Osta A (2006) "Reply to "Testing for association between MeCP2 and the brahma-associated SWI/SNF chromatin-remodeling complex" Nat Genet 38:964-67.
• Wang L, Baiocchi RA, Pal S, Mosialos G, Caligiuri M and Sif S (2005) "The BRG1- and hBRM-associated factor BAF57 induces apoptosis by stimulating expression of the cylindromatosis tumor suppressor gene" Mol Cell Biol 25(18):7953-65.
• Harikrishan KN, Chow M, Baker EK, Pal S, Bassal S, Brasacchio D, Wang L, Craig JM, Jones PL, Sif S and El-Osta A (2005) "Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing" Nat Genet 37(3):254-64.
• Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P and Sif S (2004) "Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes" Mol Cell Biol 24(21):9630-45.
• Sif S (2004) "ATP-dependent nucleosome remodeling complexes: enzymes tailored to deal with chromatin" J Cell Biochem 91(6):1087-98.
• Pal S, Yun R, Datta A, Lacomis L, Erdjument-Bromage H, Tempst P, Kumar J and Sif S (2003) "mSin3A/histone deacetylase 2- and PRMT5-containing Brg1 complex is involved in transcriptional repression of the Myc target gene cad" Mol Cell Biol 23(21):7475-87.
• Aoyagi S, Narlikar G, Zheng C, Sif S, Kingston RE and Hayes JJ (2002) "Nucleosome remodeling by the human SWI/SNF complex requires transient global disruption of histone-DNA interactions" Mol Cell Biol 22(11):3653-3662.
• Fuchs M, Gerver J, Drapkin R, Sif S, Ikura T, Ogryzko V, Lane WS, Nakatani Y and Livingston D (2001) "The p400 complex is an essential E1A transformation target" Cell 106:297-307.
• Sullivan EK, Weirich CS, Guyon JR, Sif S and Kingston RE (2001) "Transcriptional activation domains of human heat shock factor 1 recruit human SWI/SNF" Mol Cell Biol 21:5826-37.
• Sif S, Saurin AJ, Imbalzano AN and Kingston RE (2001) "Purification and characterization of mSin3A-containing Brg1 and hBrm chromatin remodeling complexes" Genes Dev 15:603-18.