Role for A-type lamins in herpesviral DNA targeting and heterochromatin modulation.
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.
Silva
Lindsey
L
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Cliffe
Anna
A
Chang
Lynne
L
Knipe
David M
DM
D000818:Animals; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D004279:DNA, Viral / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D018390:Gene Targeting; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D034904:Lamin Type A / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
D004279:DNA, Viral; D006570:Heterochromatin; D034904:Lamin Type A; D012333:RNA, Messenger; D014764:Viral Proteins