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Histone deacetylases positively regu...

Greer, Celeste B.

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Histone deacetylases positively regulate transcriptional elongation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Histone deacetylases positively regulate transcriptional elongation./
作者:	Greer, Celeste B.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
面頁冊數:	111 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.
Contained By:	Dissertation Abstracts International77-12B(E).
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10154497
ISBN:	9781369095906

Histone deacetylases positively regulate transcriptional elongation.
Greer, Celeste B.

Histone deacetylases positively regulate transcriptional elongation. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 111 p.

Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.

Thesis (Ph.D.)--Yale University, 2016.

Treatment with histone deacetylase inhibitors (HDACI) results in potent cytotoxicity of a variety of cancer cell types, and these drugs are used clinically to treat tumors. They increase acetylation of lysines in histones and other proteins. Histone acetylation is associated with active gene transcription. By increasing acetylation globally through blocking deacetylation, these drugs cause an increase in transcription of pro-apoptotic and cell cycle arrest genes. They are also known to reduce the expression of the HER2 protein in HER2+ breast cancers by blocking the transcription of ERBB2, the gene that encodes HER2. HDACI are able to block the expression of many other oncogenes in other tumor types, as well. How these drugs repress transcription is less well-understood.

ISBN: 9781369095906Subjects--Topical Terms:

634543
Pharmacology.

Histone deacetylases positively regulate transcriptional elongation.
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500 $a Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.
500 $a Advisers: Tae Hoon Kim; Benjamin Turk.
502 $a Thesis (Ph.D.)--Yale University, 2016.
520 $a Treatment with histone deacetylase inhibitors (HDACI) results in potent cytotoxicity of a variety of cancer cell types, and these drugs are used clinically to treat tumors. They increase acetylation of lysines in histones and other proteins. Histone acetylation is associated with active gene transcription. By increasing acetylation globally through blocking deacetylation, these drugs cause an increase in transcription of pro-apoptotic and cell cycle arrest genes. They are also known to reduce the expression of the HER2 protein in HER2+ breast cancers by blocking the transcription of ERBB2, the gene that encodes HER2. HDACI are able to block the expression of many other oncogenes in other tumor types, as well. How these drugs repress transcription is less well-understood.
520 $a My research shows that in addition to ERBB2, HDACI preferentially repress the transcription of other highly expressed genes in all cells and high copy number genes in HER2+ breast cancer genomes. In contrast, genes that are activated by HDACI are moderately expressed. I analyzed gene copy number in combination with steady state mRNA level measured with microarray and nascent transcription measured with global run-on sequencing (GRO-seq) in normal and breast cancer cells to show that high copy number genes are more likely to be repressed by HDACI than non-amplified genes. I have found that inhibition of histone deacetylases (HDACs) represses elongation of RNA polymerase II (RNAP2) in many genes, not only oncogenes, suggesting a regulated role in active gene transcription despite being known as transcriptional repressors. The inhibition of transcription elongation in amplified oncogenes, which promote survival and proliferation of cancer cells, helps explain the cancer-specific lethality of HDACI, and may represent a general therapeutic strategy for cancer.
520 $a Transcription elongation regulates gene expression and is a desirable target for cancer therapy. RNAP2 pause release is a regulated process involving several factors. I have investigated the involvement of important regulators of elongation in connection with HDACs. I find that elongation repression by HDACI, but not a positive transcription elongation factor b (P-TEFb) inhibitor, requires heat shock protein 90 (HSP90) activity. HDACI treatment changes the localization of elongation factors, as measured by chromatin immunoprecipitation sequencing (ChIP-seq), especially negative elongation factor (NELF), an HSP90 client complex.
520 $a Outside of coding regions, HDACI induce global changes in the topography of chromatin. The most dramatic effects are seen in intergenic regions, which contain elements that regulate gene transcription. By looking at the distribution of lysine acetylation and a chromatin post-translational modification reader protein genome-wide using ChIP-seq, I found that bromodomain-containing protein 4 (BRD4), which binds to acetyl-lysines in histone tails, is binding to sites where histone acetylation is increased upon HDACI treatment. These newly created sites are located in gene bodies and in intergenic regions, which are normally not highly acetylated. Both NELF and BRD4 have been implicated in enhancer function, and we show that sites of high enhancer RNA (eRNA) synthesis in cells require HDAC activity to create high levels of these unstable RNAs. The reduction in enhancer activity may cause the changes in the binding of elongation factors within coding regions.
520 $a Overall, I explore the pathway by which HDACs affect transcriptional elongation by RNAP2, and implicate this family of proteins in active gene transcription. This pathway affects elongation in normal and cancer transformed cells, but because the genes they selectively target in cancer cells are required for their survival and proliferation, they are of great interest for cancer treatment. I identify the protein complexes involved in the pathway by which HDACs regulate elongation. I propose that HDACs are required to maintain acetylation at proper sites, which facilitates elongation factor binding at promoters and enhancers to stimulate transcriptional elongation. This work identifies the importance on finding even better ways to target this pathway for improved treatments of cancer, and is of general interest for understanding the biological process of gene transcription.
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