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Vol. 11, No. 23,
pp. 3232-3241,
December 1, 1997
Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 1 Leiden Institute of Chemistry, Gorlaeus Laboratories, 2300 RA Leiden, The Netherlands
African trypanosomes such as Trypanosoma brucei undergo
antigenic variation in the bloodstream of their mammalian hosts by regularly changing the variant surface glycoprotein
(VSG) gene expressed. The transcribed VSG gene is
invariably located in a telomeric expression site. There are multiple
expression sites and one way to change the VSG gene expressed
is by activating a new site and inactivating the previously active one.
The mechanisms that control expression site switching are unknown, but
have been suggested to involve epigenetic regulation. We have found
previously that VSG genes in silent (but not active) expression
sites contain modified restriction endonuclease cleavage sites, and we
have presented circumstantial evidence indicating that this is
attributable to the presence of a novel modified base
-D-glucosyl-hydroxymethyluracil, or J. To directly test
this, we have generated antisera that specifically recognize
J-containing DNA and have used these to determine the precise location
of this modified thymine in the telomeric VSG expression
sites. By anti J-DNA immunoprecipitations, we found that J is present
in telomeric VSG genes in silenced expression sites and not
in actively transcribed telomeric VSG genes. J was absent from
inactive chromosome-internal VSG genes. DNA modification was
also found at the boundaries of expression sites. In the long 50-bp
repeat arrays upstream of the promoter and in the telomeric repeat
arrays downstream of the VSG gene, J was found both in silent
and active expression sites. This suggests that silencing results in a
gradient of modification spreading from repetitive DNA flanks into the
neighboring expression site sequences. In this paper, we discuss the
possible role of J in silencing of expression sites.
[Key Words: DNA modification; silencing; antigenic variation; VSG; sequence repeats]
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