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  

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Control Number  

joongbu:639986