2014
Liu, Yujie; Wang, Liqing; Han, Rongxiang; Beier, Ulf H; Akimova, Tatiana; Bhatti, Tricia; Xiao, Haiyan; Cole, Philip A; Brindle, Paul K; Hancock, Wayne W
Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function Journal Article
In: Mol Cell Biol, vol. 34, no. 21, pp. 3993-4007, 2014, ISSN: 1098-5549.
Abstract | Links | BibTeX | Tags: Animals, Cell Survival, Colitis, CREB-Binding Protein, Cyclic AMP Response Element-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Female, Forkhead Transcription Factors, GATA3 Transcription Factor, Genetic, Humans, Inbred C57BL, Male, Mice, Promoter Regions, Regulatory, Sequence Deletion, T-Lymphocytes
@article{1299979,
title = {Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function},
author = {Yujie Liu and Liqing Wang and Rongxiang Han and Ulf H Beier and Tatiana Akimova and Tricia Bhatti and Haiyan Xiao and Philip A Cole and Paul K Brindle and Wayne W Hancock},
doi = {10.1128/MCB.00919-14},
issn = {1098-5549},
year = {2014},
date = {2014-11-01},
journal = {Mol Cell Biol},
volume = {34},
number = {21},
pages = {3993-4007},
abstract = {T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. A histone/protein acetyltransferase (HAT), p300, was recently found to be important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3 to 4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose dependent and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 conserved noncoding sequence 2 (CNS2) region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells.},
keywords = {Animals, Cell Survival, Colitis, CREB-Binding Protein, Cyclic AMP Response Element-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Female, Forkhead Transcription Factors, GATA3 Transcription Factor, Genetic, Humans, Inbred C57BL, Male, Mice, Promoter Regions, Regulatory, Sequence Deletion, T-Lymphocytes},
pubstate = {published},
tppubtype = {article}
}
T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. A histone/protein acetyltransferase (HAT), p300, was recently found to be important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3 to 4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose dependent and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 conserved noncoding sequence 2 (CNS2) region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells.
Prusevich, Polina; Kalin, Jay H; Ming, Shonoi A; Basso, Manuela; Givens, Jeffrey; Li, Xin; Hu, Jianfei; Taylor, Martin S; Cieniewicz, Anne M; Hsiao, Po-Yuan; Huang, Rong; Roberson, Heather; Adejola, Nkosi; Avery, Lindsay B; Casero, Robert A; Taverna, Sean D; Qian, Jiang; Tackett, Alan J; Ratan, Rajiv R; McDonald, Oliver G; Feinberg, Andrew P; Cole, Philip A
A selective phenelzine analogue inhibitor of histone demethylase LSD1 Journal Article
In: ACS Chem Biol, vol. 9, no. 6, pp. 1284-93, 2014, ISSN: 1554-8937.
Abstract | Links | BibTeX | Tags: Animals, Blotting, Cell Survival, Cells, Cultured, DNA Methylation, Embryo, Enzyme Inhibitors, Fetus, Histone Demethylases, Histones, Humans, Mammalian, Monoamine Oxidase, Neurons, Phenelzine, Rats, Sprague-Dawley, Western
@article{1299983,
title = {A selective phenelzine analogue inhibitor of histone demethylase LSD1},
author = {Polina Prusevich and Jay H Kalin and Shonoi A Ming and Manuela Basso and Jeffrey Givens and Xin Li and Jianfei Hu and Martin S Taylor and Anne M Cieniewicz and Po-Yuan Hsiao and Rong Huang and Heather Roberson and Nkosi Adejola and Lindsay B Avery and Robert A Casero and Sean D Taverna and Jiang Qian and Alan J Tackett and Rajiv R Ratan and Oliver G McDonald and Andrew P Feinberg and Philip A Cole},
doi = {10.1021/cb500018s},
issn = {1554-8937},
year = {2014},
date = {2014-06-01},
journal = {ACS Chem Biol},
volume = {9},
number = {6},
pages = {1284-93},
abstract = {Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.},
keywords = {Animals, Blotting, Cell Survival, Cells, Cultured, DNA Methylation, Embryo, Enzyme Inhibitors, Fetus, Histone Demethylases, Histones, Humans, Mammalian, Monoamine Oxidase, Neurons, Phenelzine, Rats, Sprague-Dawley, Western},
pubstate = {published},
tppubtype = {article}
}
Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.