Aberrant heterochromatic foci are associated to deregulation of the GMCL1 gene in CH1 lymphoma B cells

ABSTRACT: Chromosome 1 pericentric heterochromatin rearrangements : potent drivers of nuclear architecture perturbations and gene deregulation in human B cell lymphoma Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence, that a distinct category of chromosomal translocation observed in human tumours – those targeting 1q12 satellite DNA - can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localised to the nuclear periphery and to arise as a consequence of long range ‘pairing’ between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localisation and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression by via long range epigenetic mechanisms. The formation of aberrant heterochromatic foci, coupled to abnormal enrichment of adjacent 2p sequences in repressive heterochromatin marks (H4K20me3, H3K9me3 and HP1), delayed replication and repositioning of the rearranged chromosome 2 to the nuclear periphery, could be associated to altered gene expression of at least those genes brought into close proximity to heterochromatin. To assess this question, global gene expression profiling was performed in the lymphoma B cells presenting the aberrant heterochromatin foci (CH1), treated or not with the histone deacetylase inhibitor, trichostatin A.

ORGANISM(S): Homo sapiens

SUBMITTER: Mary Callanan 

PROVIDER: E-GEOD-20666 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress