THE IMMUNOGLOBULIN HEAVY-CHAIN LOCUS-CONTROL REGION INCREASES HISTONEACETYLATION ALONG LINKED C-MYC GENES

In chromosome translocations characteristic of Burkitt lymphomas (BL) and murine plasmacytomas, c-myc genes become juxtaposed to immunoglobu lin heavy-chain (IgH) sequences, resulting in aberrant c-myc transcrip tion. Translocated c-myc alleles that retain the first exon exhibit in creased transcription from the normally minor c-myc promoter, P1, and increased transcriptional elongation through inherent pause sites prox imal to the major c-myc promoter, P2, We recently demonstrated that a cassette derived from four DNase I-hypersensitive sites (HS1234) in th e 3'C alpha region of the IgH locus functions as an enhancer-locus con trol region (LCR) and directs a similar pattern of deregulated express ion of linked c-myc genes in BL and plasmacytoma cell lines. Here, we report that the HS1234 enhancer-LCR mediates a widespread increase in histone acetylation along linked c-myc genes in Raji BL cells. Signifi cantly, the increase in acetylation was not restricted to nucleosomes within the promoter region but also was apparent upstream and downstre am of the transcription start sites as well as along vector sequences. Histone hyperacetylation of control c-myc genes, which was induced by the deacetylase inhibitor trichostatin A, mimics the effect of the HS 1234 enhancer on expression from the c-myc P2 promoter, but not that f rom the P1 promoter. These results suggest that the HS1234 enhancer st imulates transcription of c-myc by a combination of mechanisms. Wherea s HS1234 activates expression from the P2 promoter through a mechanism that includes increased histone acetylation, a general increase in hi stone acetylation is not sufficient to explain the HS1234-mediated act ivation of transcription from P1.