Dataset Information

Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation.

ABSTRACT: Adult stem cells, which exist throughout the body, multiply by cell division to replenish dying cells or to promote regeneration to repair damaged tissues. To perform these functions during the lifetime of organs or tissues, stem cells need to maintain their populations in a faithful distribution of their epigenetic states, which are susceptible to stochastic fluctuations during each cell division, unexpected injury, and potential genetic mutations that occur during many cell divisions. However, it remains unclear how the three processes of differentiation, proliferation, and apoptosis in regulating stem cells collectively manage these challenging tasks. Here, without considering molecular details, we propose a genetic optimal control model for adult stem cell regeneration that includes the three fundamental processes, along with cell division and adaptation based on differential fitnesses of phenotypes. In the model, stem cells with a distribution of epigenetic states are required to maximize expected performance after each cell division. We show that heterogeneous proliferation that depends on the epigenetic states of stem cells can improve the maintenance of stem cell distributions to create balanced populations. A control strategy during each cell division leads to a feedback mechanism involving heterogeneous proliferation that can accelerate regeneration with less fluctuation in the stem cell population. When mutation is allowed, apoptosis evolves to maximize the performance during homeostasis after multiple cell divisions. The overall results highlight the importance of cross-talk between genetic and epigenetic regulation and the performance objectives during homeostasis in shaping a desirable heterogeneous distribution of stem cells in epigenetic states.

SUBMITTER: Lei J

PROVIDER: S-EPMC3956188 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation.

Lei Jinzhi J Levin Simon A SA Nie Qing Q

Proceedings of the National Academy of Sciences of the United States of America 20140205 10

Adult stem cells, which exist throughout the body, multiply by cell division to replenish dying cells or to promote regeneration to repair damaged tissues. To perform these functions during the lifetime of organs or tissues, stem cells need to maintain their populations in a faithful distribution of their epigenetic states, which are susceptible to stochastic fluctuations during each cell division, unexpected injury, and potential genetic mutations that occur during many cell divisions. However, ...[more]

PMID: 24501127

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Project description:Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) infection. Mtb is one of the oldest human pathogens, and evolves mechanisms implied in human evolution. The lungs are the first organ exposed to aerosol-transmitted Mtb during gaseous exchange. Therefore, the guards of the immune system in the lungs, such as macrophages (M?s) and dendritic cells (DCs), are the most important defense against Mtb infection. There have been several studies discussing the functions of M?s and DCs during Mtb infection, but the genome-wide pathways and networks are still incomplete. Furthermore, the immune response induced by M?s and DCs varies. Therefore, we analyzed the cross-talk genome-wide genetic-and-epigenetic interspecies networks (GWGEINs) between M?s vs. Mtb and DCs vs. Mtb to determine the varying mechanisms of both the host and pathogen as it relates to M?s and DCs during early Mtb infection. First, we performed database mining to construct candidate cross-talk GWGEIN between human cells and Mtb. Then we constructed dynamic models to characterize the molecular mechanisms, including intraspecies gene/microRNA (miRNA) regulation networks (GRNs), intraspecies protein-protein interaction networks (PPINs), and the interspecies PPIN of the cross-talk GWGEIN. We applied a system identification method and a system order detection scheme to dynamic models to identify the real cross-talk GWGEINs using the microarray data of M?s, DCs and Mtb. After identifying the real cross-talk GWGEINs, the principal network projection (PNP) method was employed to construct host-pathogen core networks (HPCNs) between M?s vs. Mtb and DCs vs. Mtb during infection process. Thus, we investigated the underlying cross-talk mechanisms between the host and the pathogen to determine how the pathogen counteracts host defense mechanisms in M?s and DCs during Mtb H37Rv early infection. Based on our findings, we propose Rv1675c as a potential drug target because of its important defensive role in M?s. Furthermore, the membrane essential proteins v1098c, and Rv1696 (or cytoplasm for Rv0667), in Mtb could also be potential drug targets because of their important roles in Mtb survival in both cell types. We also propose the drugs Lopinavir, TMC207, ATSM, and GTSM as potential therapeutic treatments for Mtb infection since they target the above potential drug targets.

Dataset Information

Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation.

Publications

Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation.

Similar Datasets

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