Within chromatin, the core histone tail domains play critical roles in regu
lating the structure and accessibility of nucleosomal DNA within the chroma
tin fiber. Thus, many nuclear processes are facilitated by concomitant post
translational modification of these domains. However, elucidation of the me
chanisms by which the tails mediate such processes awaits definition of tai
l interactions within chromatin, In this study we have investigated the pri
mary DNA target of the majority of the tails in mononucleosomes. The result
s clearly show that the tails bind preferentially to "linker" DNA. outside
of the DNA encompassed by the nucleosome core. These results have important
implications for models of tail function within the chromatin fiber and fo
r in vitro structural and functional studies using nucleosome core particle
s.