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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]
상세정보
- 자료유형
- 학위논문
- Control Number
- 0016931921
- International Standard Book Number
- 9798379755508
- Dewey Decimal Classification Number
- 575
- Main Entry-Personal Name
- Jain, Naveen.
- Publication, Distribution, etc. (Imprint
- [S.l.] : University of Pennsylvania., 2023
- Publication, Distribution, etc. (Imprint
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Physical Description
- 1 online resource(198 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- General Note
- Advisor: Raj, Arjun;Bartolomei, Marisa S.
- Dissertation Note
- Thesis (Ph.D.)--University of Pennsylvania, 2023.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Summary, Etc.
- 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.
- Subject Added Entry-Topical Term
- Genetics.
- Subject Added Entry-Topical Term
- Cellular biology.
- Subject Added Entry-Topical Term
- Molecular biology.
- Index Term-Uncontrolled
- Somatic cells
- Index Term-Uncontrolled
- Pluripotency
- Index Term-Uncontrolled
- Cell-intrinsic determinants
- Index Term-Uncontrolled
- Gene expression
- Added Entry-Corporate Name
- University of Pennsylvania Cell and Molecular Biology
- Host Item Entry
- Dissertations Abstracts International. 84-12B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
- 로그인을 한후 보실 수 있는 자료입니다.
- Control Number
- joongbu:639986
MARC
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■020 ▼a9798379755508
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a575
■1001 ▼aJain, Naveen.
■24510▼aBeyond Luck of the Draw: Uncovering Cell-Intrinsic Determinants in Reprogramming Somatic Cells to Pluripotency▼h[electronic resource]
■260 ▼a[S.l.]▼bUniversity of Pennsylvania. ▼c2023
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2023
■300 ▼a1 online resource(198 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 84-12, Section: B.
■500 ▼aAdvisor: Raj, Arjun;Bartolomei, Marisa S.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aGene 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.
■590 ▼aSchool code: 0175.
■650 4▼aGenetics.
■650 4▼aCellular biology.
■650 4▼aMolecular biology.
■653 ▼aSomatic cells
■653 ▼aPluripotency
■653 ▼aCell-intrinsic determinants
■653 ▼aGene expression
■690 ▼a0369
■690 ▼a0379
■690 ▼a0307
■71020▼aUniversity of Pennsylvania▼bCell and Molecular Biology.
■7730 ▼tDissertations Abstracts International▼g84-12B.
■773 ▼tDissertation Abstract International
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16931921▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
