Premium
Two transactivation mechanisms cooperate for the bulk of HIF‐1‐responsive gene expression
Author(s) -
Kasper Lawryn H,
Boussouar Fayçal,
Boyd Kelli,
Xu Wu,
Biesen Michelle,
Rehg Jerold,
Baudino Troy A,
Cleveland John L,
Brindle Paul K
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600846
Subject(s) - biology , transactivation , gene expression , gene , genetics , regulation of gene expression , microbiology and biotechnology , computational biology
The C‐terminal activation domain (C‐TAD) of the hypoxia‐inducible transcription factors HIF‐1α and HIF‐2α binds the CH1 domains of the related transcriptional coactivators CREB‐binding protein (CBP) and p300, an oxygen‐regulated interaction thought to be highly essential for hypoxia‐responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (ΔCH1) of CBP and p300 that abrogate their interactions with the C‐TAD, revealing that the CH1 domains of CBP and p300 are genetically non‐redundant and indispensable for C‐TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of ∼35–50% of global HIF‐1‐responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA S ) accounts for ∼70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF‐responsive transcription.