A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage-specific genes in human chondrocytes.
The role of histone deacetylase 1 and 2 (HDAC1 and HDAC2) in regulating cartilage-specific gene expression was explored in primary human chondrocytes. HDAC1 and HDAC2 protein levels were elevated in chondrocytes from osteoarthritic patients, consistent with a down-regulation of some cartilage marker genes. When expressed in these cells, HDAC1 and HDAC2 repressed aggrecan and collagen 2(alpha1) expression but differed in their repression of collagen 9(alpha1), collagen 11(alpha1), dermatopontin, and cartilage oligomeric matrix protein (COMP). To identify the basis of these differences between HDAC1 and HDAC2, their carboxy-terminal domains (CTDs) were deleted, which led to proteins that retained enzymatic activity but were unable to repress cartilage gene expression. Further, exchange of the CTDs between HDAC1 and HDAC2 led to proteins that were enzymatically active but displayed altered target gene specificity, indicating that these CTDs can function independently of HDAC enzymatic activity, to target the HDACs to specific genes. The Snail transcription factor was identified as a mediator of HDAC1 and HDAC2 repression of the collagen 2(alpha1) gene, via its interaction with the HDAC1 and 2 CTDs. The data indicate that the CTD serves a novel function within HDAC1 and HDAC2, to mediate repression of cartilage-specific gene expression in human chondrocytes.
Hong
Sohee
S
Cartilage Molecular Genetics Group, Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Derfoul
Assia
A
Pereira-Mouries
Lucilia
L
Hall
David J
DJ
D000595:Amino Acid Sequence; D002356:Cartilage; D019902:Chondrocytes; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010003:Osteoarthritis / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases