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Power laws govern mitochondrial optimization of inheritable cellular memory and fate decision

Cheikhi, Amin (2017) Power laws govern mitochondrial optimization of inheritable cellular memory and fate decision. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cheikhi, Aminamc165@pitt.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPitt, Brucebrucep@pitt.edubrucep
Committee CoChairBarchowsky, Aaronaab20@pitt.eduaab20
Committee MemberAmbrosio, Fabrisiafaa7@pitt.edufaa7
Committee MemberSt Croix, Claudettecls13@pitt.educls13
Committee MemberStraub, Adamastraub@pitt.eduastraub
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: Graduate 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: 29 Jun 2017 23:39
URI: http://d-scholarship.pitt.edu/id/eprint/32276

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