Cheikhi, Amin
(2017)
Power laws govern mitochondrial optimization of inheritable cellular memory and fate decision.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Chronic environmental exposure to arsenic in drinking water is a major public health concern affecting the health of more than 130 million people worldwide. In addition to causing cancer and non-cancer diseases, arsenic causes muscle weakness and dysfunction. We found that arsenic targets muscle stem cell mitochondrial functionality to impair muscle maintenance and regeneration. Stem cell behavior was determined by their epigenetic memory. Although mitochondrial remodeling is inescapable for successful differentiation and pluripotency reprogramming and mitochondria-derived outputs shape cellular epigenetic landscape, their role in the regulation of cellular memory is poorly understood. Arsenic is a mitochondrial stressor and epigenetic modifier that alters stem-cell fate determination making it an excellent tool to determine the mitochondrial contribution to regulation of cellular memory and fate decisions. Using a model of myogenic differentiation, we imprinted a memory of arsenite-induced stress into myogenic reserve cells (RC) and monitored the fate of their progeny in arsenic-free medium. Phenotyping of primed RC revealed inherited aberrant mitochondrial dynamics that limited self-renewal capacity and enhanced their proliferation; trapping them in a poised state. Non-Gaussian statistics demonstrated that nuclear protein profiles and morphometrics were distributed as power-laws, indicating the presence of critical self-organization at the cell population level. Using graph theory, we modeled the mitochondria and showed an increased connectivity of the primed RC progeny mitochondrial networks. We identified crucial interplay of H2A.Z acetylation with RNA polymerase II at bivalent chromatin domains that define chromatin state and transcriptional plasticity of the primed RC. Importantly, the intervention by mitochondria-targeted XJB-5-131 fully restored mitochondrial functionality and dynamics, RC cellular phenotypic identity, nuclear morphometrics, and epigenetic regulation that reset RC memory including histone modifications. Collectively, this work demonstrated that poising of chromatin regulation and cellular memory are fundamentally contingent on mitochondrial functionality and dynamics. Furthermore, we provided an innovative conceptual framework whereby cellular memory and cell fate are statistical properties defined at the cell population level by intricate mechanisms integrated at the mitochondrial level and governed by power laws. Significantly, the beneficial effects of XJB-5-131 suggest a window of opportunity for preventing or reverting disease resulting from stem cell dysfunction.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
29 June 2017 |
| Date Type: |
Publication |
| Defense Date: |
17 April 2017 |
| Approval Date: |
29 June 2017 |
| Submission Date: |
30 May 2017 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
123 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Environmental and Occupational Health |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Arsenic, Muscle stem cell , Mitochondria |
| Date Deposited: |
29 Jun 2017 23:39 |
| Last Modified: |
01 May 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/32276 |
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