Cystic fibrosis (CF), an autosomal recessive disorder, is caused by a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) gene product. The CFTR gene (CFTR) is regulated by promoter sequences that give rise to low levels of tissue-specific gene transcription. The overall objective of this proposal is to determine the mechanisms that direct transcription of CFTR to learn how CFTR transcription is related to the pathophysiology of CF. The acetylation of core histones within the nucleosome is associated with the formation of """"""""open"""""""" chromatin, necessary for transcriptional activation. Furthermore, histone deacetylation is associated with repressive, or """"""""closed"""""""", chromatin structure. The alteration in chromatin is critical for the control of gene transcription in vivo. We have demonstrated that CFTR transcription is directly associated with histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, but it is unclear how histone acetylation regulates CFTR transcription. We propose that histone acetylation direct the transcription of CFTR. Currently, the mechanisms that direct histone acetylation to a specific gene and that regulate gene transcription are not well understood. First, we wish to test the hypotheses that regulation of CFTR transcription in vivo is mediated through histone acetylation. Based on our previous work we will examine whether transcription factors ATF1 and CBF/NF-Y and the histone acetyltransferase coactivator proteins, p300/CREB-binding protein (p300/CBP) and p300/CBP-associated factor (PCAF) mediate histone acetylation of CFTR. We will determine the function of histone acetylation in the regulation of CFTR transcription. CFTR is a target of histone acetylation when the CFTR promoter contains an inverted CCAAT (Y-box) element in vivo. Both CFTR transcript initiation and cAMP-mediated CFTR transcription regulation require the Y-box element, suggesting that this element, by interacting with specific transcription factors, may be essential to the modification of chromatin in CFTR. Second, we will test the hypothesis that CCAAT displacement protein (CDP) recruits HDACs to CFTR in vivo and is regulated by acetylation. CDP, a critical trans-acting regulator of CFTR transcriptional repression, is directly associated with a co-repressor complex composed of specific HDAC activity. CDP interacts with the co-activator p300/CBP. Furthermore, CDP is regulated by acetyltransferase (FAT) activities of p300/CBP and PCAF. We plan to test the role of CDP as a substrate for acetyltransferase and deacetylase function and to determine whether the acetylation of CDP effect transcription of CFTR.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL067099-01
Application #
6319415
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Banks-Schlegel, Susan P
Project Start
2001-07-05
Project End
2005-04-30
Budget Start
2001-07-05
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$296,625
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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