2 options
Systems biology of gene regulation across scales : from single molecules to cellular identities / Ian A. Mellis.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Mellis, Ian A., author.
- Language:
- English
- Subjects (All):
- Molecular biology.
- Bioengineering.
- Genetics.
- Genomics and computational biology--Penn dissertations.
- Penn dissertations--Genomics and computational biology.
- Local Subjects:
- Molecular biology.
- Bioengineering.
- Genetics.
- Genomics and computational biology--Penn dissertations.
- Penn dissertations--Genomics and computational biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (126 pages)
- Contained In:
- Dissertations Abstracts International 81-09B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Gene regulation takes many forms and is responsible for phenotypes at the scale of individual molecules up through the scale of complex tissue functions. At the smallest level, single-base modifications of individual mRNA molecules transcribed from the same gene can lead to functionally different protein products. In the first chapter of this thesis, I develop a new method, inoFISH, and associated analytical tools to visualize and quantify RNA editing with single molecule resolution in single mammalian cells. Using this new method in conjunction with mathematical modeling I show that the heterogeneity of single-cell mRNA editing rates across a population depends on the gene of interest. Further, I characterize subcellular localization patterns of edited and unedited mRNAs. At the other end of the spectrum, the regulation of transcriptome-wide patterns of gene expression can underpin cellular identities. In the second chapter of this thesis I develop a new experimental design and analytical framework for prioritizing lists of transcription factors that can be used for directed changes of cellular identity. With Perturbation Panel Profiling (P3), I show that cardiomyocyte lineage-driving transcription factors are more frequently up-regulated, or "perturbable", than other highly expressed transcription factor genes. I subsequently demonstrate that a known cocktail of cardiomyocyte-perturbable transcription factors enables cardiac transdifferentiation of several types of human fibroblasts. Lastly I extend perturbability-based selection of transcription factors to another biological context, i.e., fibroblast reprogramming to pluripotency. I show that fibroblast-perturbable factor knockdown often enables more efficient fibroblast reprogramming. Together, my thesis makes critical steps toward understanding and engineering gene regulation through the development of a diverse array of methods, experimental designs, and analytical frameworks.
- Notes:
- Source: Dissertations Abstracts International, Volume: 81-09, Section: B.
- Includes supplementary digital materials.
- Advisors: Raj, Arjun; Committee members: Junhyong Kim; Marisa Bartolomei; Christopher Brown; Tuuli Lappalainen.
- Department: Genomics and Computational Biology.
- Ph.D. University of Pennsylvania 2019.
- Local Notes:
- School code: 0175
- ISBN:
- 9781392734889
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
- This item must not be sold to any third party vendors.
The Penn Libraries is committed to describing library materials using current, accurate, and responsible language. If you discover outdated or inaccurate language, please fill out this feedback form to report it and suggest alternative language.