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]
- Material Type
- 단행본
- 0016931714
- Date and Time of Latest Transaction
- 20240214100107
- ISBN
- 9798379711825
- DDC
- 575
- Author
- Chivu, Alexandra Georgiana.
- Title/Author
- The Molecular Interplay and Evolution of Promoter-Proximal Pausing and Its Relationship to Histone Modifications - [electronic resource]
- Publish Info
- [S.l.]: : Cornell University., 2023
- Publish Info
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- Material Info
- 1 online resource(209 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- General Note
- Advisor: Danko, Charles G.
- 학위논문주기
- Thesis (Ph.D.)--Cornell University, 2023.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Abstracts/Etc
- 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.
- Subject Added Entry-Topical Term
- Genetics.
- Subject Added Entry-Topical Term
- Molecular biology.
- Subject Added Entry-Topical Term
- Molecular chemistry.
- Index Term-Uncontrolled
- Histone
- Index Term-Uncontrolled
- RNA Polymerase II
- Index Term-Uncontrolled
- Gene regulation
- Index Term-Uncontrolled
- Post-translational modifications
- Index Term-Uncontrolled
- DNA sequence
- Added Entry-Corporate Name
- Cornell University Genetics Genomics and Development
- Host Item Entry
- Dissertations Abstracts International. 84-12B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
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- 소장사항
-
202402 2024
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