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The Molecular Interplay and Evolution of Promoter-Proximal Pausing and Its Relationship to Histone Modifications- [electronic resource]

자료유형: 학위논문파일 국외

최종처리일시: 20240214100107

ISBN: 9798379711825

DDC: 575

저자명: Chivu, Alexandra Georgiana.

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.