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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Medical Biochemistry Study Section (MEDB)
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Banks-Schlegel, Susan P
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Mount Sinai School of Medicine
Schools of Medicine
New York
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Di Cecilia, Serena; Zhang, Fan; Sancho, Ana et al. (2016) RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells. Cancer Res 76:5615-5627
Aguilo, Francesca; Li, SiDe; Balasubramaniyan, Natarajan et al. (2016) Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1?. Cell Rep 14:479-492
Aguilo, Francesca; Di Cecilia, Serena; Walsh, Martin J (2016) Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease. Curr Top Microbiol Immunol 394:29-39
Sancho, Ana; Li, SiDe; Paul, Thankam et al. (2015) CHD6 regulates the topological arrangement of the CFTR locus. Hum Mol Genet 24:2724-32
Li, SiDe; Banck, Michaela; Mujtaba, Shiraz et al. (2010) p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One 5:e10486
Banck, Michaela S; Li, Side; Nishio, Hitomi et al. (2009) The ZNF217 oncogene is a candidate organizer of repressive histone modifiers. Epigenetics 4:100-6
Tan, Cheryl C; Sindhu, K V; Li, Side et al. (2008) Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription. Proc Natl Acad Sci U S A 105:7472-7
Paul, Thankam; Li, SiDe; Khurana, Sanjeev et al. (2007) The epigenetic signature of CFTR expression is co-ordinated via chromatin acetylation through a complex intronic element. Biochem J 408:317-26
Banck, Michaela S; Beaven, Simon W; Narla, Goutham et al. (2006) KLF6 degradation after apoptotic DNA damage. FEBS Lett 580:6981-6
Beutler, Andreas S; Li, SiDe; Nicol, Rebekka et al. (2005) Carbamazepine is an inhibitor of histone deacetylases. Life Sci 76:3107-15

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