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Bart M. G. Smits, PhD

Bart M. G. Smits, PhD

Assistant Professor
Department of Pathology and Laboratory Medicine
Medical University of South Carolina
Bioengineering Building, Rm 411
68 President Street
Charleston, SC 29425

Office phone: 843-876-2293
Lab phone: 843-876-2239 or 843-876-2294

EDUCATION:

MS: Molecular Biology/Molecular Genetics, Faculty of Biology, Utrecht University, The Netherlands, 2001
PhD: Functional Genomics, Hubrecht Institute, Utrecht University, The Netherlands, 2005
Postdoctoral Fellow: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 2006-2010

RESEARCH INTERESTS:

The susceptibility to common cancers, such as breast and prostate cancer has a strong genetic component. The heritable portion of cancer susceptibility consists of many genetic elements. Over the last couple of years, through genome-wide association studies (GWAS) many novel cancer-associated variants have been found that are low-penetrance and common in the population. Many of these variants are located to non-protein coding genomic regions. It is currently poorly understood how such variants affect cancer risk. Understanding mechanisms underlying common cancer susceptibility variants will in the future lead to the development of effective cancer prevention or intervention strategies that will potentially benefit many people at risk. My lab is interested in understanding mechanisms underlying common, non-coding cancer susceptibility variants on the genetic/genomic level and on the cellular/tissue level in the process of carcinogenesis.

We use state-of-the-art molecular tools:

  • gene expression level analysis – RNA-seq, TaqMan assays
  • chromatin interaction analysis – chromosome conformation capture (3C) assay
  • chromatin immunoprecipitation – ChIP-seq, ChIP-PCR

We use novel genetic engineering approaches to model human cancer susceptibility variants in mice and rats:

  • Mutagenic Insertion and Chromosome Engineering Resource (MICER) vector-assisted genome editing
  • Zinc-finger nuclease (ZFN)- and Transcription Activator-Like Effector Nuclease (TALEN)-mediated genome editing

We study the engineered alleles in rodent cancer models:

  • Chemical mammary carcinogenesis in rats
  • Retroviral vector-mediated mammary carcinogenesis in rats
  • Transgenic mouse breast and prostate cancer models
  • Tissue transplantation assays to study cell-of-origin of cancer phenotype modulation
Example of mutagenic insertion and chromosome engineering resource (MICER) vector-assisted targeting in mouse ES-cells.

Figure 1: Example of mutagenic insertion and chromosome engineering resource (MICER) vector-assisted targeting in mouse ES-cells. The deleted region is depicted as a red horizontal bar. At the indicated positions, a compatible pair of MICER vectors was placed on the same chromosome (~450 Kb spacing), such that upon Cre-recombinase-driven excision in the ES-cell stage, a functional Hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene was formed, which allowed for selection of a correctly targeted ES-cell clone. Upon Cre-recombination a large deletion (mega-deletion) was induced. The MHPP vector contained Agouti (A), HPRT exons 3-9, loxP (grey triangle) and a Puromycin resistance gene (puro); The MHPN vector contained a Neomycin resistance gene (neo), loxP (grey triangle), HPRT exons 1 and 2, and Tyrosinase (TYR).


Figure 2: Example of a non-protein coding region orthologous to a human cancer-associated non-coding (gene desert) region targeted in the mouse.

Figure 2: Example of a non-protein coding region orthologous to a human cancer-associated non-coding (gene desert) region targeted in the mouse. The deleted mouse region is entirely non-protein coding and encompasses elements orthologous to human haplotype blocks associated with prostate (blue), breast (pink) and colon (brown) cancer, but not bladder cancer (yellow).

SELECTED PUBLICATIONS:

  1. Smits BM, Haag JD, Rissman AI, Sharma D, Tran A, Schoenborn AA, Baird RC, Peiffer DS, Leinweber DQ, Muelbl MJ, Meilahn AL, Eichelberg MR, Leng N, Kendziorski C, John MC, Powers PA, Alexander CM, Gould MN. The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation. In revision
  2. Smits BM, Traun BD, Devries TL, Tran A, Samuelson D, Haag JD, Gould M. An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a. Nucleic Acids Res. (2012) Jan;40(1):132-47
  3. Sharma D, Eichelberg MR, Haag JD, Meilahn, AL, Muelbl MJ, Schell K, Smits BM, Gould MN. Effective flow cytometric phenotyping of cells using minimal amounts of antibody. Biotechniques (2012) Jul;53(1):57-60
  4. Smits BM, Sharma D, Samuelson DJ, Woditschka S, Haag JD, Gould MN. The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions. Breast Cancer Res. (2011) Aug 16;13(4):R81 (See also: Editorial by Blackburn, Breast Cancer Res. (2011) 13:112
  5. Sharma D, Smits BM*, Eichelberg MR, Meilahn A, Muelbl MJ, Haag JD, Gould MN. Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One. (2011) 6(10):e26145
  6. Smits BM and Gould MN. “Gene targeting in the rat? Cut it out!”. Mol Interv. (2009) Oct;9(5):226-229
  7. Smits BM, Cotroneo MS, Haag JD, Gould MN. Genetically engineered rat models for breast cancer. Breast Diseases (2007) 28:53-61
  8. Smits BM, Cuppen E. Rat genetics: the next episode. Trends Genet. (2006) Feb28; 22: 232-240
  9. Smits BM, Mudde JB, Van de Belt J, Verheul M, Olivier J, Guryev V, Ellenbroek BA, Plasterk RH, Cuppen E. Generation of mutant and knockout rats by ENU-driven target-selected mutagenesis. Pharmacogenet. Genomics (2006) Mar;16(3):159-69
  10. Smits BM, Guryev V, Zeegers D, Wedekind D., Hedrich HJ, Cuppen, E. Wild rat-based SNP discovery. BMC Genomics (2005) Nov 29;6:170
  11. Smits BM, Peters TA, Mul JD, Croes HJ, Fransen JA, Beynon AJ, Guryev V, Plasterk RH, Cuppen E. Identification of a rat model for Usher syndrome type 1B using ENU-mutagenesis-driven forward genetics. Genetics (2005) Aug;170(4):1887-96
  12. Smits BM, van Zutphen BF, Plasterk RH, Cuppen E. Genetic variation in coding regions between and within commonly used inbred rat strains. Genome Res. (2004) Jul;14(7):1285-90.
  13. Smits BM, D'Souza UM, Berezikov E, Cuppen E, Sluyter F. Identifying polymorphisms in the Rattus norvegicus D3 dopamine receptor gene and regulatory region. Genes Brain Behav. (2004) Jun;3(3):138-48.
  14. Smits BM, Mudde J, Plasterk RH, Cuppen E. Target-selected mutagenesis of the rat. Genomics (2004) 83(2):332-4.


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