東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back

Switch To: Labeled | MARC Mode | ISBD

Investigating Mechanisms of Pathogen...

Williams, Katherine Elizabeth.

Linked to FindBook

Google Book

Amazon

博客來

Investigating Mechanisms of Pathogenesis in Facioscapulohumeral Muscular Dystrophy.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigating Mechanisms of Pathogenesis in Facioscapulohumeral Muscular Dystrophy./
Author:	Williams, Katherine Elizabeth.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	215 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
Subject:	Bioinformatics. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28540967
ISBN:	9798522927851

Investigating Mechanisms of Pathogenesis in Facioscapulohumeral Muscular Dystrophy.
Williams, Katherine Elizabeth.

Investigating Mechanisms of Pathogenesis in Facioscapulohumeral Muscular Dystrophy. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 215 p.

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

Thesis (Ph.D.)--University of California, Irvine, 2021.

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

Facioscapulohumeral muscular dystrophy (FSHD) is a rare disease with characteristic weakness in facial and periscapular muscles which progresses to additional muscle groups. FSHD is caused by the misexpression of the embryonic transcription factor DUX4 in muscle cells. In 95% of FSHD patients, a series of macrorepeats preceding DUX4 is contracted and derepressed in part through loss of DNA methylation. In the remaining FSHD patients, the repeats are derepressed but not contracted, and 80% of these patients have a mutation in SMCHD1, which regulates DNA methylation in these repeats. DUX4 is involved in zygotic genome activation (ZGA) when it activates a number of transcription factors and chromatin remodelers, such as DUXA, LEUTX and ZSCAN4, as well as long terminal repeats (LTRs), such as ERVL-MaLRs, which are also activated in FSHD. DUX4 expression in patient muscle cells is sparse (0.5% of myotube nuclei), but its expression in only a few nuclei is sufficient to activate target gene expression in multiple nuclei within a multinucleated muscle cell, which is sustained when DUX4 is no longer present. My work has focused on understanding progression of FSHD at a molecular level both into different muscle groups and following DUX4 activation. I used single nucleus RNA sequencing to understand the contribution of individual nuclei to gene dysregulation following DUX4 expression. I identified nuclei with native expression of DUX4, as well as two populations of nuclei with high and low expression of DUX4-induced genes. The high group appears to perpetuate pathogenesis and has higher expression of genes related to the cell cycle despite the nuclei coming from cells in G0. I also found that DUX4 is coexpressed with only a subset of its target genes, while the DUX4 homolog DUXA is expressed with a wider set of targets. To understand why certain muscle groups are commonly or less affected in FSHD, I assayed DNA methylation and gene expression in different muscle groups. Genes induced during myogenesis in FSHD have higher expression in commonly affected muscle groups despite their promoters having high DNA methylation. Muscle groups differ in expression and DNA methylation of transcription factors key to developmental patterning and specification that may contribute to susceptibility to FSHD. Finally, I explored the role of DUXA as a potential regulator of DUX4 target genes following their initial activation. I found that DUXA depletion is sufficient to lower expression of DUX4 target genes including LTRs. I also identified a set of genes which are induced along with DUX4 during myogenesis in FSHD2 that are not induced following DUXA depletion. I have thus identified a candidate regulator of FSHD gene dysregulation and candidate contributors to differential muscle group susceptibility in FSHD.

ISBN: 9798522927851Subjects--Topical Terms:

553671
Bioinformatics.
Subjects--Index Terms:

Pathogenesis

Investigating Mechanisms of Pathogenesis in Facioscapulohumeral Muscular Dystrophy.
LDR:03975nmm a2200361 4500 001 2283656
005 20211115071523.5
008 220723s2021 ||||||||||||||||| ||eng d
020 $a 9798522927851
035 $a (MiAaPQ)AAI28540967
035 $a AAI28540967
040 $a MiAaPQ $c MiAaPQ
100 1 $a Williams, Katherine Elizabeth. $3 3562657
245 1 0 $a Investigating Mechanisms of Pathogenesis in Facioscapulohumeral Muscular Dystrophy.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 215 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
500 $a Advisor: Mortazavi, Ali.
502 $a Thesis (Ph.D.)--University of California, Irvine, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Facioscapulohumeral muscular dystrophy (FSHD) is a rare disease with characteristic weakness in facial and periscapular muscles which progresses to additional muscle groups. FSHD is caused by the misexpression of the embryonic transcription factor DUX4 in muscle cells. In 95% of FSHD patients, a series of macrorepeats preceding DUX4 is contracted and derepressed in part through loss of DNA methylation. In the remaining FSHD patients, the repeats are derepressed but not contracted, and 80% of these patients have a mutation in SMCHD1, which regulates DNA methylation in these repeats. DUX4 is involved in zygotic genome activation (ZGA) when it activates a number of transcription factors and chromatin remodelers, such as DUXA, LEUTX and ZSCAN4, as well as long terminal repeats (LTRs), such as ERVL-MaLRs, which are also activated in FSHD. DUX4 expression in patient muscle cells is sparse (0.5% of myotube nuclei), but its expression in only a few nuclei is sufficient to activate target gene expression in multiple nuclei within a multinucleated muscle cell, which is sustained when DUX4 is no longer present. My work has focused on understanding progression of FSHD at a molecular level both into different muscle groups and following DUX4 activation. I used single nucleus RNA sequencing to understand the contribution of individual nuclei to gene dysregulation following DUX4 expression. I identified nuclei with native expression of DUX4, as well as two populations of nuclei with high and low expression of DUX4-induced genes. The high group appears to perpetuate pathogenesis and has higher expression of genes related to the cell cycle despite the nuclei coming from cells in G0. I also found that DUX4 is coexpressed with only a subset of its target genes, while the DUX4 homolog DUXA is expressed with a wider set of targets. To understand why certain muscle groups are commonly or less affected in FSHD, I assayed DNA methylation and gene expression in different muscle groups. Genes induced during myogenesis in FSHD have higher expression in commonly affected muscle groups despite their promoters having high DNA methylation. Muscle groups differ in expression and DNA methylation of transcription factors key to developmental patterning and specification that may contribute to susceptibility to FSHD. Finally, I explored the role of DUXA as a potential regulator of DUX4 target genes following their initial activation. I found that DUXA depletion is sufficient to lower expression of DUX4 target genes including LTRs. I also identified a set of genes which are induced along with DUX4 during myogenesis in FSHD2 that are not induced following DUXA depletion. I have thus identified a candidate regulator of FSHD gene dysregulation and candidate contributors to differential muscle group susceptibility in FSHD.
590 $a School code: 0030.
650 4 $a Bioinformatics. $3 553671
650 4 $a Cellular biology. $3 3172791
650 4 $a Developmental biology. $3 592588
650 4 $a Laboratories. $3 531588
650 4 $a DNA methylation. $3 3560639
650 4 $a Disease. $3 705846
650 4 $a Mutation. $3 837917
650 4 $a Muscular dystrophy. $3 1615100
650 4 $a Tendons. $3 548816
650 4 $a Biology. $3 522710
650 4 $a Genomics. $3 600531
650 4 $a Research & development--R&D. $3 3554335
650 4 $a Genomes. $3 592593
650 4 $a Cell cycle. $3 766119
650 4 $a Neurons. $3 588699
650 4 $a Myogenesis. $3 2130888
650 4 $a Gene expression. $3 643979
650 4 $a Fibroblasts. $3 1573241
650 4 $a Awards & honors. $3 3560943
650 4 $a Musculoskeletal system. $3 548825
650 4 $a Aging. $3 543123
650 4 $a College students. $3 537393
650 4 $a Teaching assistants. $3 3562658
650 4 $a Methods. $3 3560391
650 4 $a Pathogenesis. $3 3561735
650 4 $a Stem cells. $3 767761
650 4 $a Biotechnology. $3 571461
650 4 $a Transcription factors. $3 669191
653 $a Pathogenesis
653 $a Facioscapulohumeral muscular dystrophy
690 $a 0715
690 $a 0379
690 $a 0758
690 $a 0493
690 $a 0306
710 2 $a University of California, Irvine. $b Biological Sciences - Ph.D.. $3 3189591
773 0 $t Dissertations Abstracts International $g 83-02B.
790 $a 0030
791 $a Ph.D.
792 $a 2021
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28540967