Beyond Luck of the Draw: Uncovering Cell-Intrinsic Determinants in Reprogramming Somatic Cells to Pluripotency- [electronic resource]
Beyond Luck of the Draw: Uncovering Cell-Intrinsic Determinants in Reprogramming Somatic Cells to Pluripotency- [electronic resource]
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214100348
- ISBN
- 9798379755508
- DDC
- 575
- 저자명
- Jain, Naveen.
- 서명/저자
- Beyond Luck of the Draw: Uncovering Cell-Intrinsic Determinants in Reprogramming Somatic Cells to Pluripotency - [electronic resource]
- 발행사항
- [S.l.]: : University of Pennsylvania., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(198 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- 주기사항
- Advisor: Raj, Arjun;Bartolomei, Marisa S.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Gene expression variability between genetically identical single cells, previously viewed as random noise, can drive functional biological behaviors. These phenotypes, remarkably, can even be dictated by transient differences in a handful of key genes. Currently, we know little of how gene expression variability may affect reprogramming somatic cells into induced pluripotent stem cells (iPSCs) by expression of the four "Yamanaka" factors of OCT4, KLF4, SOX2, and MYC (OKSM). Even in homogenous conditions in isogenic cells, only a very rare (1%) subset of cells admit reprogramming, and the characteristics of this subset remain unknown. The prevailing view is that this subset is determined by random chance, mediated by the probabilistic binding and activity of the OKSM factors early in reprogramming. However, recent demonstrations that related cells share the same reprogramming outcome implies the existence of pre-existing, intrinsic differences that drive reprogramming fates and that are heritable across cell division. Here, we leverage a retrospective clone tracing method to identify and characterize individual human fibroblast cells "primed" to become iPSCs in the initial population before exposure to OKSM. These primed fibroblasts showed gene expression markers of increased cell cycle speed and decreased fibroblast activation, both of which we demonstrate directly affect reprogramming outcomes. Furthermore, knockdown of a fibroblast activation factor identified by our analysis led to increased reprogramming efficiency, identifying it as a barrier to reprogramming. Changing the frequency of reprogramming by inhibiting the activity of epigenetic modifiers led to an enlarging of the pool of cells that were primed for reprogramming, indicating that the primed state is not fixed but context-dependent. Our results show that even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not. Furthermore, we provide evidence in support of a model of reprogramming that is predominantly deterministic instead of stochastic.
- 일반주제명
- Genetics.
- 일반주제명
- Cellular biology.
- 일반주제명
- Molecular biology.
- 키워드
- Somatic cells
- 키워드
- Pluripotency
- 키워드
- Gene expression
- 기타저자
- University of Pennsylvania Cell and Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 84-12B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
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