1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in 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 translocations 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 localized 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 localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms.
Fournier
Alexandra
A
INSERM U823, Institut Albert Bonniot, Grenoble, France.
McLeer-Florin
Anne
A
Lefebvre
Christine
C
Duley
Samuel
S
Barki
Leila
L
Ribeyron
Juliana
J
Alboukadel
Kassambara
K
Hamaidia
Sieme
S
Granjon
Aurélie
A
Gressin
Rémy
R
Lajmanovich
Alicia
A
Bonnefoix
Thierry
T
Chauvelier
Stéphanie
S
Debernardi
Alexandra
A
Rousseaux
Sophie
S
de Fraipont
Florence
F
Figeac
Martin
M
Kerckaert
Jean-Pierre
JP
De Vos
John
J
Usson
Yves
Y
Delaval
Katia
K
Grichine
Alexei
A
Vourc'h
Claire
C
Khochbin
Saadi
S
Feil
Robert
R
Leroux
Dominique
D
Callanan
Mary B
MB
D002467:Cell Nucleus / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006570:Heterochromatin / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D014178:Translocation, Genetic
D006570:Heterochromatin