Faculty


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  • Michael Hebert, PhD

     hebert_michael

    Professor
    Phone: (601) 984-1526
    E-mail: mhebert@umc.edu

    Personal website:
    http://openwetware.org/wiki/Hebert_Lab

    Background

    • Graduated in 1997 - Department of Biology, Georgia State University (Dr. John Houghton, mentor)
    • Postdoctoral studies (1997-98) - Department of Pathology and Laboratory Medicine, Emory University (with Dr. Bratin Saha)
    • Postdoctoral studies (1998-2002) - Department of Genetics, Case Western Reserve University (with Dr. Greg Matera)
    • Assistant professor (2002-07) - Department of Biochemistry, University of Mississippi Medical Center
    • Associate Professor (2007-10) - Department of Biochemistry, UMMC
    • Professor (2010-present) - Department of Biochemistry, UMMC

    Research interests

    Our work centers upon understanding the functional organization of the nucleus. In particular, we are interested in understanding how certain human diseases alter nuclear efficiency. The nucleus contains a myriad of dynamic, highly organized domains, territories and bodies. All of these structures somehow work together; seamlessly allowing important nuclear activities, such as RNA synthesis and processing, to occur in an efficient manner. In certain disease states, the organization of the nucleus is altered. We hypothesize that diseases which disrupt the functional organization of the nucleus adversely affect ribonucleoprotein (RNP) maturation, resulting in decreased pre-mRNA and rRNA processing.

    One nuclear structure altered by some diseases is the Cajal body (CB). Various diseases are correlated with the disruption of the CB or alteration in its protein composition. Two examples are Spinal Muscular Atrophy (SMA) and Machado-Joseph disease. In Machado-Joseph disease, CBs are tethered to large inclusions caused by an expanded polyglutamine tract mutation in the protein ataxin-3. In spinal muscular atrophy (SMA), the composition of the CB is altered because an important protein, known as SMN, is no longer enriched in this structure. SMN is crucial for the cytoplasmic phase of small nuclear RNP (snRNP) biogenesis and localizes in the nucleus to the CB. It is possible that SMN chaperones newly imported snRNPs (which are needed for pre-mRNA splicing) to the CB where they are modified.ataxin2.jpg

    We are also conducting experiments designed to understand the normal cellular dialogue that occurs between some subnuclear domains. For example, it has been known for some time that Cajal bodies and another nuclear structure, known as the PML body, occasionally abut one another. We have found that CBs and PML bodies can simultaneously associate near U2 snRNA gene loci. It is possible that such an arrangement facilitates the transcription of this gene and experiments are underway to confirm this hypothesis. Additionally, since Cajal bodies are especially prevalent in cancer cells, identification and characterization of proteins that induce the formation of this structure may lead to novel cancer therapeutics.  

    CB-PML-U2-1.jpgCajal bodies and PML bodies can associate with the same U2 gene locus. HeLa cells were subjected to antibody staining to mark the location of CBs (red) and PML bodies (blue), followed by DNA FISH using an U2 gene probe (green). The arrow marks an association between CBs, PML bodies and an U2 gene (inset) in four different cells.

    In separate studies, we have developed a reporter system to screen small molecules that may benefit patients with Friedreich's ataxia. This disease is caused by a tri-nucleotide repeat expansion in a gene that encodes a vital mitochondrial protein known as frataxin. We have identified several compounds that increase frataxin expression and are currently testing these compounds in patient tissue. We are also conducting a very small pilot study in which patients will be treated with one promising compound our work has identified may be beneficial to those suffering from this insidious disease.

    In summary, our work seeks to understand nuclear function, with particular emphasis on splicing and transcription efficiency.

    We thank the following organizations for providing support for our research: Muscular Dystrophy Association, National Ataxia Foundation, Friedreich's Ataxia Research Alliance and Luckyday Foundation.

    Recent publications

    • Hebert, MD, PubMed search 

    • Gilder AS, Do PM, Carrero ZI, Cosman AM, Broome HJ, Velma V, Martinez LA, Hebert MD. "Coilin participates in the suppression of RNA polymerase I in response to cisplatin induced DNA damage." Mol Biol Cell. 2011 Feb 2. [Epub ahead of print] PMID: 21289084 [PubMed - as supplied by publisher]
    • Velma V, Carrero ZI, Cosman AM, Hebert MD. "Coilin interacts with Ku proteins and inhibits in vitro non-homologous DNA end joining." FEBS Lett. 2010 Dec 1;584(23):4735-9. Epub 2010 Nov 9. PMID: 21070772 [PubMed - indexed for MEDLINE]
    •  Hebert MD. "Phosphorylation and the Cajal body: modification in search of function." Arch Biochem Biophys. 2010 Apr 15;496(2):69-76. Epub 2010 Mar 1. Review. PMID: 20193656 [PubMed - indexed for MEDLINE]
    • Bidwell GL 3rd, Whittom AA, Thomas E, Lyons D, Hebert MD, Raucher D. "A thermally targeted peptide inhibitor of symmetrical dimethylation inhibits cancer-cell proliferation." Peptides. 2010 May;31(5):834-41. Epub 2010 Feb 16. PMID: 20167239 [PubMed - indexed for MEDLINE]
    • Toyota CG, Davis MD, Cosman AM, Hebert MD. "Coilin phosphorylation mediates interaction with SMN and SmB." Chromosoma. 2010 Apr;119(2):205-15. Epub 2009 Dec 8. PMID: 19997741 [PubMed - indexed for MEDLINE] Free PMC Article Free full text Related citations
    • Hearst SM, Gilder AS, Negi SS, Davis MD, George EM, Whittom AA, Toyota CG, Husedzinovic A, Gruss OJ, Hebert MD. "Cajal-body formation correlates with differential coilin phosphorylation in primary and transformed cell lines." J Cell Sci. 2009 Jun 1;122(Pt 11):1872-81. Epub 2009 May 12. PMID: 19435804 [PubMed - indexed for MEDLINE] Free PMC Article
    • D'Souza DR, Wei J, Shao Q, Hebert MD, Subramony SH, Vig PJ (2006). Tissue transglutaminase crosslinks ataxin-1: Possible role in SCA1 pathogenesis. Neuroscience Lett. 409, 5-9.
    • L. Grant, J. Sun, H. Xu, S. H. Subramony, J. B. Chaires and M.D. Hebert (2006). Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia. FEBS Letters 580, 5399-5405.
    • Jun Sun, Hongzhi Xu, S.H. Subramony and Michael D. Hebert (2005). Interactions between Coilin and PIASy partially link Cajal bodies to PML bodies. Journal of Cell Science 118, 4995-5003. 
    • Xu, H., Somers, Z. B., Robinson, M. L., 2nd and Hebert, M. D. (2005b). Tim50a, a nuclear isoform of the mitochondrial Tim50, interacts with proteins involved in snRNP biogenesis. BMC Cell Biol 6, 29.  
    • Hebert M.D., Shpargel K.B., Ospina J.K., Tucker K.E. and Matera A.G. Coilin methylation regulates nuclear body formation. Developmental Cell. 2002 Sept 3: 329-337.  
    • Xu, H., Pillai, R. S., Azzouz, T. N., Shpargel, K. B., Kambach, C., Hebert, M. D., Schumperli, D. and Matera, A. G. (2005a). The C-terminal domain of coilin interacts with Sm proteins and U snRNPs. Chromosoma 114, 155-66.  
    • Xu, H. and Hebert, M. D. (2005). A novel EB-1/AIDA-1 isoform, AIDA-1c, interacts with the Cajal body protein coilin. BMC Cell Biol 6, 23. 
    • Dundr, M., Hebert, M. D., Karpova, T. S., Stanek, D., Xu, H., Shpargel, K. B., Meier, U. T., Neugebauer, K. M., Matera, A. G. and Misteli, T. (2004). In vivo kinetics of Cajal body components. J Cell Biol 164, 831-42.