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The Molecular Interplay and Evolution of Promoter-Proximal Pausing and Its Relationship to Histone Modifications- [electronic resource]
The Molecular Interplay and Evolution of Promoter-Proximal Pausing and Its Relationship to Histone Modifications- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214100107
- ISBN
- 9798379711825
- DDC
- 575
- 서명/저자
- The Molecular Interplay and Evolution of Promoter-Proximal Pausing and Its Relationship to Histone Modifications - [electronic resource]
- 발행사항
- [S.l.]: : Cornell University., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(209 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- 주기사항
- Advisor: Danko, Charles G.
- 학위논문주기
- Thesis (Ph.D.)--Cornell University, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Gene regulation is a crucial aspect of cellular biology, and promoter-proximal pausing of RNA Polymerase II (Pol II) plays a critical role in this process. During pausing, Pol II stalls 20-50bp downstream from transcription start sites and is regulated by a complex interplay between internal and external cues, including interactions with the NELF and DSIF protein complexes. In turn, Pol II pausing is known to influence chromatin processes such as histone post-translational modifications (PTMs). To better understand the relationship between PTMs and transcription, we developed a machine learning tool that predicts histone marks abundance using PRO-seq data with high accuracy. Our results suggest that active histone modifications are highly correlated with transcription, implying that histone marks may play a role in regulating transcription or that transcription may impact the placement of these marks. We further explored this relationship by perturbing transcription using drug treatments and observed that most active marks were lost at transcription start sites within one hour of treatment, supporting a transcription-centric model.Next, we sought to investigate the evolution of pausing as an essential step enabling a novel layer of transcription control in metazoans. To accomplish this, we measured nascent transcription in 20 extant organisms representing diverse branches in the tree of life. We found that pausing first evolved in a common ancestor of Metazoans and coinciding with the evolution of NELF. In mammals, depletion of NELF by degron tagging reverts a "focal" pause to an ancestral "proto-paused"-like state observed in plants that is driven in part by DNA sequence. We propose that the evolution of a localized Pol II promoter-proximal pausing resulted in the collapse of a rate-limiting step in transcription to a single location at each gene. Using the well-established heat shock system, we show that this centralization of Pol II signal at a pause site allows transcription factors to release Pol II into productive elongation, providing a new target for gene-specific regulation. Our findings provide new insights into gene regulation and the evolution of regulatory complexity, which may have enabled the evolution of complex multicellular organisms.
- 일반주제명
- Genetics.
- 일반주제명
- Molecular biology.
- 일반주제명
- Molecular chemistry.
- 키워드
- Histone
- 키워드
- Gene regulation
- 키워드
- DNA sequence
- 기타저자
- Cornell University Genetics Genomics and Development
- 기본자료저록
- Dissertations Abstracts International. 84-12B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■006m o d
■007cr#unu||||||||
■020 ▼a9798379711825
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a575
■1001 ▼aChivu, Alexandra Georgiana.▼0(orcid)0000-0001-8875-3530
■24510▼aThe Molecular Interplay and Evolution of Promoter-Proximal Pausing and Its Relationship to Histone Modifications▼h[electronic resource]
■260 ▼a[S.l.]:▼bCornell University. ▼c2023
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2023
■300 ▼a1 online resource(209 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 84-12, Section: B.
■500 ▼aAdvisor: Danko, Charles G.
■5021 ▼aThesis (Ph.D.)--Cornell University, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aGene regulation is a crucial aspect of cellular biology, and promoter-proximal pausing of RNA Polymerase II (Pol II) plays a critical role in this process. During pausing, Pol II stalls 20-50bp downstream from transcription start sites and is regulated by a complex interplay between internal and external cues, including interactions with the NELF and DSIF protein complexes. In turn, Pol II pausing is known to influence chromatin processes such as histone post-translational modifications (PTMs). To better understand the relationship between PTMs and transcription, we developed a machine learning tool that predicts histone marks abundance using PRO-seq data with high accuracy. Our results suggest that active histone modifications are highly correlated with transcription, implying that histone marks may play a role in regulating transcription or that transcription may impact the placement of these marks. We further explored this relationship by perturbing transcription using drug treatments and observed that most active marks were lost at transcription start sites within one hour of treatment, supporting a transcription-centric model.Next, we sought to investigate the evolution of pausing as an essential step enabling a novel layer of transcription control in metazoans. To accomplish this, we measured nascent transcription in 20 extant organisms representing diverse branches in the tree of life. We found that pausing first evolved in a common ancestor of Metazoans and coinciding with the evolution of NELF. In mammals, depletion of NELF by degron tagging reverts a "focal" pause to an ancestral "proto-paused"-like state observed in plants that is driven in part by DNA sequence. We propose that the evolution of a localized Pol II promoter-proximal pausing resulted in the collapse of a rate-limiting step in transcription to a single location at each gene. Using the well-established heat shock system, we show that this centralization of Pol II signal at a pause site allows transcription factors to release Pol II into productive elongation, providing a new target for gene-specific regulation. Our findings provide new insights into gene regulation and the evolution of regulatory complexity, which may have enabled the evolution of complex multicellular organisms.
■590 ▼aSchool code: 0058.
■650 4▼aGenetics.
■650 4▼aMolecular biology.
■650 4▼aMolecular chemistry.
■653 ▼aHistone
■653 ▼aRNA Polymerase II
■653 ▼aGene regulation
■653 ▼aPost-translational modifications
■653 ▼aDNA sequence
■690 ▼a0369
■690 ▼a0431
■690 ▼a0307
■71020▼aCornell University▼bGenetics, Genomics and Development.
■7730 ▼tDissertations Abstracts International▼g84-12B.
■773 ▼tDissertation Abstract International
■790 ▼a0058
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16931714▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
