東華大學圖書館 |

Transcription Factors as Direct Mediators of Homeostasis and Defense.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Transcription Factors as Direct Mediators of Homeostasis and Defense./
作者:	Kim, Daniel Jong-Woong.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	102 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
標題:	Molecular biology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28002969
ISBN:	9798522947521

Transcription Factors as Direct Mediators of Homeostasis and Defense.
Kim, Daniel Jong-Woong.

Transcription Factors as Direct Mediators of Homeostasis and Defense. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 102 p.

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--Yale University, 2021.

This item must not be sold to any third party vendors.

Metazoan signaling is typically conceived as a cascade of specialized proteins transducing environmental stimuli into differential expression of genes. In this thesis, we study two transcription factors that more directly mediate cellular responses involved in homeostasis and defense through somewhat less traditional mechanisms.First, we investigated the aryl hydrocarbon receptor (AhR) which is a transcription factor that both binds ligands containing aromatic hydrocarbon rings and directly induces a pleiotropic transcriptional repertoire. In addition to binding environmental toxins like TCDD, AhR also binds a variety of natural ligands generated by tryptophan catabolism originating from the host, microbiota, or diet. In our current understanding, the vast majority of natural AhR ligands are agonists, and the few antagonists that have been characterized are low in affinity and not present at physiologically relevant concentrations in humans. Yet, the vast majority of people do not exhibit symptoms of AhR hyperstimulation - which includes birth defects, anemia, and fatty liver - indicating that there may be a high affinity, physiological antagonist that has yet to be identified.Deficiencies of vitamin B12 and folic acid (FA) present with a similar clinical picture as AhR hyperstimulation, and each vitamin contains an aromatic hydrocarbon ring moiety that has not yet been functionally characterized. Given these observations, we assessed whether B12 and FA antagonize AhR to alleviate symptoms of vitamin deficiency. In Chapter 2, we report that B12 and FA bind competitively to the ligand binding domain (LBD) of AhR, suppress AhR nuclear localization, and decrease transcriptional activity at xenobiotic responsive elements (XREs) present in target gene promoters. In vivo, we found that B12, FA, and their aryl hydrocarbon moieties were able to rescue mice from cleft palates, anemia, and fatty liver induced by TCDD exposure. Furthermore, B12- and FA-deficient mice exhibited higher AhR transcriptional activity and accumulation of erythroid progenitors at baseline, and in the case of FA-deficient mice, both of these changes were dependent on functional AhR. Finally, by analyzing RNA-Seq data from The Cancer Genome Atlas (TCGA), we observed that samples with deficient B12 and FA uptake pathways have higher expression of AhR transcriptional targets and lower expression of developmental pathways whose deficiencies have already been linked with birth defects. In contrast, samples deficient in enzymes known to interact with B12 and FA (and are currently thought to mediate the symptoms of deficiency) did not show significant difference in expression of either of these gene sets.Alongside AhR, we also investigated RUNX transcription factors and their less conventional roles in binding and repressing viral genes. Mammalian RUNX1 and RUNX3 are lineage-defining transcription factors for nociceptive and proprioceptive sensory neurons, respectively, in the dorsal root ganglia (DRG). Given the role of RUNX1 in binding HIV-1 LTR and reinforcing viral latency in T cells, we hypothesized that RUNX transcription factors in DRG may also bind and transcriptionally repress the genomes of HSV1 and HSV2 - DNA viruses that classically establish latency in DRG neurons. In Chapter 3, we report that RUNX consensus binding sequences (CBSs) are uniquely enriched among genomes of herpesviruses, but not those of non-herpesviruses. Through in vitro infections, we verified that overexpressed RUNX1 binds to putative CBSs, represses viral gene expression, and decreases overall infection.These studies broaden our understanding of how AhR and RUNX1 directly mediate host homeostasis and defense. By further investigating the roles of AhR and RUNX1 in aging and latent states of other herpesviruses, respectively, future work can help reveal broader implications these transcription factors may have for human health.

ISBN: 9798522947521Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Aryl hydrocarbon Receptor

Transcription Factors as Direct Mediators of Homeostasis and Defense.
LDR:05264nmm a2200457 4500 001 2282882
005 20211022115749.5
008 220723s2021 ||||||||||||||||| ||eng d
020 $a 9798522947521
035 $a (MiAaPQ)AAI28002969
035 $a AAI28002969
040 $a MiAaPQ $c MiAaPQ
100 1 $a Kim, Daniel Jong-Woong. $3 3561716
245 1 0 $a Transcription Factors as Direct Mediators of Homeostasis and Defense.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 102 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
500 $a Advisor: Iwasaki, Akiko;Medzhitov, Ruslan.
502 $a Thesis (Ph.D.)--Yale University, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Metazoan signaling is typically conceived as a cascade of specialized proteins transducing environmental stimuli into differential expression of genes. In this thesis, we study two transcription factors that more directly mediate cellular responses involved in homeostasis and defense through somewhat less traditional mechanisms.First, we investigated the aryl hydrocarbon receptor (AhR) which is a transcription factor that both binds ligands containing aromatic hydrocarbon rings and directly induces a pleiotropic transcriptional repertoire. In addition to binding environmental toxins like TCDD, AhR also binds a variety of natural ligands generated by tryptophan catabolism originating from the host, microbiota, or diet. In our current understanding, the vast majority of natural AhR ligands are agonists, and the few antagonists that have been characterized are low in affinity and not present at physiologically relevant concentrations in humans. Yet, the vast majority of people do not exhibit symptoms of AhR hyperstimulation - which includes birth defects, anemia, and fatty liver - indicating that there may be a high affinity, physiological antagonist that has yet to be identified.Deficiencies of vitamin B12 and folic acid (FA) present with a similar clinical picture as AhR hyperstimulation, and each vitamin contains an aromatic hydrocarbon ring moiety that has not yet been functionally characterized. Given these observations, we assessed whether B12 and FA antagonize AhR to alleviate symptoms of vitamin deficiency. In Chapter 2, we report that B12 and FA bind competitively to the ligand binding domain (LBD) of AhR, suppress AhR nuclear localization, and decrease transcriptional activity at xenobiotic responsive elements (XREs) present in target gene promoters. In vivo, we found that B12, FA, and their aryl hydrocarbon moieties were able to rescue mice from cleft palates, anemia, and fatty liver induced by TCDD exposure. Furthermore, B12- and FA-deficient mice exhibited higher AhR transcriptional activity and accumulation of erythroid progenitors at baseline, and in the case of FA-deficient mice, both of these changes were dependent on functional AhR. Finally, by analyzing RNA-Seq data from The Cancer Genome Atlas (TCGA), we observed that samples with deficient B12 and FA uptake pathways have higher expression of AhR transcriptional targets and lower expression of developmental pathways whose deficiencies have already been linked with birth defects. In contrast, samples deficient in enzymes known to interact with B12 and FA (and are currently thought to mediate the symptoms of deficiency) did not show significant difference in expression of either of these gene sets.Alongside AhR, we also investigated RUNX transcription factors and their less conventional roles in binding and repressing viral genes. Mammalian RUNX1 and RUNX3 are lineage-defining transcription factors for nociceptive and proprioceptive sensory neurons, respectively, in the dorsal root ganglia (DRG). Given the role of RUNX1 in binding HIV-1 LTR and reinforcing viral latency in T cells, we hypothesized that RUNX transcription factors in DRG may also bind and transcriptionally repress the genomes of HSV1 and HSV2 - DNA viruses that classically establish latency in DRG neurons. In Chapter 3, we report that RUNX consensus binding sequences (CBSs) are uniquely enriched among genomes of herpesviruses, but not those of non-herpesviruses. Through in vitro infections, we verified that overexpressed RUNX1 binds to putative CBSs, represses viral gene expression, and decreases overall infection.These studies broaden our understanding of how AhR and RUNX1 directly mediate host homeostasis and defense. By further investigating the roles of AhR and RUNX1 in aging and latent states of other herpesviruses, respectively, future work can help reveal broader implications these transcription factors may have for human health.
590 $a School code: 0265.
650 4 $a Molecular biology. $3 517296
650 4 $a Cellular biology. $3 3172791
650 4 $a Environmental science. $3 677245
650 4 $a Genetics. $3 530508
650 4 $a Public health. $3 534748
650 4 $a Environmental health. $3 543032
650 4 $a Toxicology. $3 556884
650 4 $a DNA methylation. $3 3560639
650 4 $a Infections. $3 1621997
650 4 $a Physiology. $3 518431
650 4 $a Birth defects. $3 3561718
650 4 $a Vitamin deficiency. $3 3561719
650 4 $a Hydrocarbons. $3 697428
650 4 $a Vitamin B. $3 3561720
650 4 $a Binding sites. $3 3560349
650 4 $a Immunology. $3 611031
650 4 $a Families & family life. $3 3422406
650 4 $a Diet. $3 626002
650 4 $a Genomes. $3 592593
650 4 $a Metabolism. $3 541349
650 4 $a Liver diseases. $3 1615081
650 4 $a Mutagenesis. $3 754710
650 4 $a Proteins. $3 558769
650 4 $a Homeostasis. $3 657244
650 4 $a Anemia. $3 684804
650 4 $a Gene expression. $3 643979
650 4 $a Herpes viruses. $3 3561721
650 4 $a Lymphocytes. $3 895384
650 4 $a Ligands. $3 686413
650 4 $a Enzymes. $3 520899
650 4 $a Roles. $3 3559999
650 4 $a Transcription factors. $3 669191
653 $a Aryl hydrocarbon Receptor
653 $a Folic Acid
653 $a Vitamin B12
653 $a Transcription factors
653 $a Homeostasis
653 $a Metazoan signaling
690 $a 0307
690 $a 0379
690 $a 0470
690 $a 0573
690 $a 0383
690 $a 0768
690 $a 0369
690 $a 0982
690 $a 0719
710 2 $a Yale University. $b Immunobiology in MD/PhD Program. $3 3561717
773 0 $t Dissertations Abstracts International $g 83-02B.
790 $a 0265
791 $a Ph.D.
792 $a 2021
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28002969