Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats.
HLCS (holocarboxylase synthetase) is a nuclear protein that catalyses the binding of biotin to distinct lysine residues in chromatin proteins. HLCS-dependent epigenetic marks are over-represented in repressed genomic loci, particularly in repeats. Evidence is mounting that HLCS is a member of a multi-protein gene repression complex, which determines its localization in chromatin. In the present study we tested the hypothesis that HLCS interacts physically with N-CoR (nuclear receptor co-repressor) and HDAC1 (histone deacetylase 1), thereby contributing toward the removal of H3K9ac (Lys⁹-acetylated histone H3) gene activation marks and the repression of repeats. Physical interactions between HLCS and N-CoR, HDAC1 and a novel splicing variant of HDAC1 were confirmed by co-immunoprecipitation, limited proteolysis and split luciferase complementation assays. When HLCS was overexpressed, the abundance of H3K9ac marks decreased by 50% and 68% in LTRs (long terminal repeats) 15 and 22 respectively in HEK (human embryonic kidney)-293 cells compared with the controls. This loss of H3K9ac marks was linked with an 83% decrease in mRNA coding for LTRs. Similar patterns were seen in pericentromeric alpha satellite repeats in chromosomes 1 and 4. We conclude that interactions of HLCS with N-CoR and HDACs contribute towards the transcriptional repression of repeats, presumably increasing genome stability.
*Department of Nutrition and Health Sciences, Ruth Leverton Hall, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, U.S.A.
Dandan
D
Liu
*Department of Nutrition and Health Sciences, Ruth Leverton Hall, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, U.S.A.
Janos
J
Zempleni
D000107:Acetylation; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D015415:Biomarkers / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D063185:Epigenetic Repression; D005816:Genetic Complementation Test; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D015415:Biomarkers; D006657:Histones; D050505:Mutant Proteins; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D010446:Peptide Fragments; D011994:Recombinant Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases