Posttranslational modification of
histones is known to regulate
chromatin structure and transcriptional activity, and the nuclear lamina is thought to serve as a site for
heterochromatin maintenance and transcriptional silencing. In this report, we show that the nuclear lamina can also play a role in the downregulation of
heterochromatin and in gene activation. Herpes simplex virus
DNA initiates replication in replication compartments near the inner edge of the nucleus, and
histones are excluded from these structures. To define the role of nuclear
lamins in HSV replication, we examined HSV
infection in wild-type and A-type
lamin-deficient (Lmna-/-) murine embryonic fibroblasts (MEFs). In Lmna-/- cells, viral replication compartments are reduced in size and fail to target to the nuclear periphery, as observed in WT cells.
Chromatin immunoprecipitation and immunofluorescence studies demonstrate that HSV
DNA is associated with increased
heterochromatin in Lmna-/- MEFs. These results argue for a functional role for A-type
lamins as viral gene expression, DNA replication, and growth are reduced in Lmna-/- MEFs, with the greatest effect on viral replication at low multiplicity of
infection. Thus,
lamin A/C is required for targeting of the viral genome and the reduction of
heterochromatin on viral promoters during lytic
infection. The nuclear lamina can serve as a molecular scaffold for
DNA genomes and the
protein complexes that regulate both
euchromatin and
heterochromatin histone modifications.