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The Latency-Associated Nuclear Antigen Interacts with MeCP2 and Nucleosomes through Separate Domains

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells express the latency-associated nuclear antigen (LANA) involved in the regulation of host and viral gene expression and maintenance of the KSHV latent episome. Performance of these diverse functions involves a 7-amino-acid chromatin-binding motif (CBM) situated at the amino terminus of LANA that is capable of binding directly to nucleosomes. LANA interacts with additional chromatin components, including methyl-CpG-binding protein 2 (MeCP2). Here, we show that the carboxy-terminal DNA-binding/dimerization domain of LANA provides the principal interaction with MeCP2 but that this association is modulated by the CBM. Both domains are required for LANA to colocalize with MeCP2 at chromocenters, regions of extensive pericentric heterochromatin that can be imaged by fluorescence microscopy. Within MeCP2, the methyl-CpG-binding domain (MBD) is the primary determinant for chromatin localization and acts together with the adjacent repression domains (the transcription repression domain [TRD] and the corepressor-interacting domain [CRID]) to redirect LANA to chromocenters. MeCP2 facilitates repression by LANA bound to the KSHV terminal repeats, a function that requires the MeCP2 C terminus in addition to the MBD and CRID/TRD. LANA and MeCP2 can also cooperate to stimulate transcription of the human E2F1 promoter, which lacks a LANA DNA-binding sequence, but this function requires both the N and C termini of LANA. The ability of LANA to establish multivalent interactions with histones and chromatin-binding proteins such as MeCP2 would enable LANA to direct regulatory complexes to specific chromosomal sites and thereby achieve stable reprogramming of cellular gene expression in latently infected cells.