| Research projects: Epigenetic regulation in facio-scapulo-humeral dystrophy
Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy with prevalence of 1 in 20,000. The disease has been causally related to deletion of tandemly-arrayed 3.3 kb repeat units (D4Z4) on chromosome 4q35 possibly affecting chromatin organization and nearby gene expression. Consistently, it has been observed that a number of genes mapping at 4q35 are over-expressed in the FSHD affected muscle. Thus, the current hypothesis to explain FSHD onset is that the reduction of D4Z4 tandemly repeated units to a critical threshold might induce the over-expression of 4q35 genes and, as a consequence, triggers FSHD pathogenesis. We study the chromatin organization of the 4q35 locus and its role in epigenetic regulation of genes involved in FSHD. References: Dmitriev P., Lipinski, M. and VASSETZKY, Y (2009) Pearls in junk: dissecting the molecular pathogenesis of facioscapulohumeral muscular dystrophy. Neuromuscular Disorder, 19:17-20. Medline Full text Pirozhkova, I., Petrov, A. Laoudj, D., Lipinski, M., and VASSETZKY, Y.S., (2008) Spatial organization of the 4q35 locus suggests a role for 4qA/4qB marker in FSHD, PLoS One, 3: e3389. Medline Full text
Petrov A., Allinne J., Pirozhkova, I., Laoudj, D., Lipinski, M., and VASSETZKY, Y.S.(2008) Nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity: implications for the facioscapulohumeral dystrophy. Genome Research, 18:39-45. Medline Full text
Petrov, A. Pirozhkova, I., Carnac, G., Laoudj, D., Lipinski, M., and VASSETZKY, Y.S. (2006) Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts. Proc. Natl. Acad. Sci. USA, 103:6982-6987. Medline Full text
Nuclear architecture and cancer
Lymphoma is a cancer involving cells of the immune system; over 35 different subtypes exist. We are particularly interested in two lymphoma types, Burkitt lymphoma (BL), and mantle cell lymphoma (MCL).
Most BLs carry a translocation of the c-myc oncogene from chromosome 8 to either the immunoglobulin (Ig) heavy-chain region on chromosome 14 [t(8;14)] or one of the light-chain loci on chromosome 2 (kappa light chain) [t(8;2)] or chromosome 22 (lambda light chain) [t(8;22)]. This translocation juxtaposes Ig gene enhancer (IGH, 14q32) with the c-myc locus, leading to an overexpression of a number of genes, including the c-myc gene. The translocation site may be as far as 700 kb from the IGH enhancer, which makes direct regulation unlikely. MCL is closely associated with the translocation (11;14)(q13;q32). This translocation juxtaposes Ig heavy chain gene (IGH, 14q32) sequences with the /BCL-1 /locus, leading to an overexpression of a number of genes, including the cyclin D1 gene (CCND1). However, CCND1 overexpression alone is not sufficient for hematopoietic transformation since mice transgenic for cyclin D1 do not develop MCL. Recent transcriptome studies have revealed that several genes located in the vicinity of the breakpoint on chromosome 11 are overexpressed in MCL cells. This general transcription upregulation might be due to epigenetic processes as in the BL. Chromosomes 8 and 11 are located in a largely heterochromatic region of the nucleus, while chromosome 14 is found in a more euchromatic context. We propose that the t(11 ; 14) and t(8 ; 14) translocations induce the transposition of the 11q13 or 8q22 loci from an heterochromatic to an euchromatic region of the nucleus. This movement could then cause the overexpression of the genes located on 11q13 and 8q22. We have studied the localization of the rearranged (11;14)(q13;q32) locus in MCL and have found that the translocated loci are relocalized within the nucleus towards the nuclear center form the peripheral regions. The biochemical and epigenetic mechanisms which may be activated by such translocations are currently under study. References: Razin, S.V., Iarovaia, O. ,Sjakste, N., Sjakste, T., Bagdoniene, L., Rynditch, A.V., Eivazova, E.R., Lipinski, M., and VASSETZKY, Y.S. (2007) Chromatin domains and regulation of transcription. J. Mol. Biol, 369:597-607. Medline Full text Razin, S.V., Petrov, A., Hair, A., and VASSETZKY, Y.S. (2004) Chromatin Domains and Territories: a Flexible Rigidity. Critical Reviews in Eukaryotic Gene Expression, 14: 79–88. Medline Full text |