Altered chromatin modifications in AML1/RUNX1 breakpoint regions involved in (8;21) translocation.
The RUNX1/AML1 gene is the most frequent target for chromosomal translocation, and often identified as a site for reciprocal rearrangement of chromosomes 8 and 21 in patients with acute myelogenous leukemia. Virtually all chromosome translocations in leukemia show no consistent homologous sequences at the breakpoint regions. However, specific chromatin elements (DNase I and topoisomerase II cleavage) have been found at the breakpoints of some genes suggesting that structural motifs are determinant for the double strand DNA-breaks. We analyzed the chromatin organization at intron 5 of the RUNX1 gene where all the sequenced breakpoints involved in t(8;21) have been mapped. Using chromatin immunoprecipitation assays we show that chromatin organization at intron 5 of the RUNX1 gene is different in HL-60 and HeLa cells. Two distinct features mark the intron 5 in cells expressing RUNX1: a complete lack or significantly reduced levels of Histone H1 and enrichment of hyperacetylated histone H3. Strikingly, induction of DNA damage resulted in formation of t(8;21) in HL-60 but not in HeLa cells. Taken together, our results suggest that H1 depletion and/or histone H3 hyperacetylation may have a linkage with an increase susceptibility of specific chromosomal regions to undergo translocations.
Departamento de Bioquímica y Biología Molecular, Universidad de Concepción, Concepción, Chile.
Marcela
M
Stuardo
Milka
M
Martinez
Karla
K
Hidalgo
Martin
M
Montecino
Amjad
A
Javed
Jane B
JB
Lian
Gary S
GS
Stein
Janet L
JL
Stein
Soraya E
SE
Gutiérrez
D000107:Acetylation; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D019457:Chromosome Breakage; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D018922:HL-60 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D011485:Protein Binding; D014178:Translocation, Genetic / Q000235:genetics*
D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones