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Epigenetic Control of Neural Crest Development and Neural Crest Derived Tumors
Epigenetic Control of Neural Crest Development and Neural Crest Derived Tumors
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151047
- ISBN
- 9798384077527
- DDC
- 574
- 서명/저자
- Epigenetic Control of Neural Crest Development and Neural Crest Derived Tumors
- 발행사항
- [Sl] : University of California, San Francisco, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 109 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Includes supplementary digital materials.
- 주기사항
- Advisor: Bush, Jeffrey.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2024.
- 초록/해제
- 요약The neural crest is a multipotent transient cell population that migrates, proliferates, and differentiates in vertebrate embryogenesis and gives rises to a cornucopia of tissue derivatives such as craniofacial bone and cartilage, peripheral nerves, and glia. Congenital malformations including cleft palate and craniosynostosis arise from aberrant development of cranial neural crest cells and their derivatives. Neural crest derived tumors of Schwann cell lineages can arise from single genomic hits in the form of NF2 loss. Considering the low genomic burden of many neural crest derived tumors, we hypothesized that epigenetic regulators, which normally specify cell lineages and maintain cell fates in embryonic development, are mis-regulated in adult neural crest derived tissues, contributing to tumorigenesis and differential tumor radiation responses.Here we use mouse genetics and single cell sequencing to investigate how PRC2, a histone methyltransferase broadly involved in gene repression and maintenance of pluripotency in development, is involved in epigenetic control of post-otic neural crest derivates. We identified Eed, a PRC2 core subunit, as a potent regulator of craniofacial development. Eed deletion in post-migratory neural crest cells was perinatal lethal and knockout embryos presented with severe craniofacial abnormalities consistent with impaired differentiation of osteoblast derivatives. Using targeted primary cell culture gene expression analysis and unbiased scRNA-seq, we discovered changes in transcription factors involved in the proliferation and differentiation of neural crest derivatives including loss of Sox transcription factors and increase in Hox genes. Strikingly, we found an expansion of undifferentiated mesenchymal stem cells and decrease in differentiated osteoblast cells, indicating Eed controls proper differentiation of mesenchymal derivatives that comprise craniofacial structures. Taken together, we establish the embryonic, cellular, and molecular consequences of Eed loss in neural crest derived craniofacial tissues.Next, we investigated more broadly how epigenetic regulation contributes to cancer of neural crest derived cells including the tumorigenesis of schwannomas and schwannoma radiation responses. Using bulk and single-cell bioinformatics, functional genomic approaches, and mechanistic validation, we discovered schwannomas comprise 2 molecular subgroups marked by activation of neural crest signaling pathways or enrichment of immune cells in response to radiotherapy. CRISPRi radiation screening in human schwannoma cells identified the lysine demethylases KDM1A and KDM5C as drivers of radioresistance or radiosensitivity, respectively. Lastly, we integrated single-nuclei ATAC, RNA, and CRISPRi perturbation to identify chromatin accessibility motifs that drive schwannoma cell state evolution and radiation responses.
- 일반주제명
- Developmental biology
- 일반주제명
- Genetics
- 일반주제명
- Cellular biology
- 일반주제명
- Neurosciences
- 일반주제명
- Molecular biology
- 키워드
- Neural crest
- 기타저자
- University of California, San Francisco Cell Biology
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151047
■006m o d
■007cr#unu||||||||
■020 ▼a9798384077527
■035 ▼a(MiAaPQ)AAI31140904
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aCasey-Clyde, Timothy.▼0(orcid)0000-0002-9281-4073
■24510▼aEpigenetic Control of Neural Crest Development and Neural Crest Derived Tumors
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a109 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aIncludes supplementary digital materials.
■500 ▼aAdvisor: Bush, Jeffrey.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2024.
■520 ▼aThe neural crest is a multipotent transient cell population that migrates, proliferates, and differentiates in vertebrate embryogenesis and gives rises to a cornucopia of tissue derivatives such as craniofacial bone and cartilage, peripheral nerves, and glia. Congenital malformations including cleft palate and craniosynostosis arise from aberrant development of cranial neural crest cells and their derivatives. Neural crest derived tumors of Schwann cell lineages can arise from single genomic hits in the form of NF2 loss. Considering the low genomic burden of many neural crest derived tumors, we hypothesized that epigenetic regulators, which normally specify cell lineages and maintain cell fates in embryonic development, are mis-regulated in adult neural crest derived tissues, contributing to tumorigenesis and differential tumor radiation responses.Here we use mouse genetics and single cell sequencing to investigate how PRC2, a histone methyltransferase broadly involved in gene repression and maintenance of pluripotency in development, is involved in epigenetic control of post-otic neural crest derivates. We identified Eed, a PRC2 core subunit, as a potent regulator of craniofacial development. Eed deletion in post-migratory neural crest cells was perinatal lethal and knockout embryos presented with severe craniofacial abnormalities consistent with impaired differentiation of osteoblast derivatives. Using targeted primary cell culture gene expression analysis and unbiased scRNA-seq, we discovered changes in transcription factors involved in the proliferation and differentiation of neural crest derivatives including loss of Sox transcription factors and increase in Hox genes. Strikingly, we found an expansion of undifferentiated mesenchymal stem cells and decrease in differentiated osteoblast cells, indicating Eed controls proper differentiation of mesenchymal derivatives that comprise craniofacial structures. Taken together, we establish the embryonic, cellular, and molecular consequences of Eed loss in neural crest derived craniofacial tissues.Next, we investigated more broadly how epigenetic regulation contributes to cancer of neural crest derived cells including the tumorigenesis of schwannomas and schwannoma radiation responses. Using bulk and single-cell bioinformatics, functional genomic approaches, and mechanistic validation, we discovered schwannomas comprise 2 molecular subgroups marked by activation of neural crest signaling pathways or enrichment of immune cells in response to radiotherapy. CRISPRi radiation screening in human schwannoma cells identified the lysine demethylases KDM1A and KDM5C as drivers of radioresistance or radiosensitivity, respectively. Lastly, we integrated single-nuclei ATAC, RNA, and CRISPRi perturbation to identify chromatin accessibility motifs that drive schwannoma cell state evolution and radiation responses.
■590 ▼aSchool code: 0034.
■650 4▼aDevelopmental biology
■650 4▼aGenetics
■650 4▼aCellular biology
■650 4▼aNeurosciences
■650 4▼aMolecular biology
■653 ▼aCraniofacial development
■653 ▼aEmbryonic development
■653 ▼aEpigenetic regulation
■653 ▼aNeural crest
■653 ▼aPolycomb repressive complex 2
■690 ▼a0758
■690 ▼a0369
■690 ▼a0379
■690 ▼a0317
■690 ▼a0307
■71020▼aUniversity of California, San Francisco▼bCell Biology.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160600▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
