Abstract
It is becoming increasingly clear that di erences in DNA sequence can not be the sole carrier of the phenotypic di erentiation that arises when a cell expresses di erent genes to di erent degrees. A simple example, such as the cells of the human body, clearly shows that cells carrying the same genomic material can show quiet diverse phenotypes characterized by organ speci c gene expression patterns. The mechanisms responsible for this phenotypic plasticity are characterized as epigenetic, as they in ict their e ect \epi-" (Greek for \above" or \on top") of the genetic code. For a gene regulatory mechanism to be classi ed as epigenetic, it is required that it is self-sustainable in the sense that the governed gene expression or repression should prevail for the lifetime of the cell and must be inherited by possible daughter cells.
An example of epigenetic di erentiation is the bistable switch of phage TP901-1, in which the devotion to a distinct state is governed by a small network of trans-acting factors. TP901-1 infects lactococcal bacteria and either exploit the host for the production of new phage leading to the death of the host, or become integrated on the host genome as a non-lethal tag-along during subsequent cell divisions. The switch of the phage, responsible for the dedicated choice, is a small DNA fragment comprising two promoters set back-to-back and their adjacent genes. The gene products work as regulators of the promoters, joining the regulatory loop of the switch. In its lethal path, it is proposed that the switch should implement an interaction between the two antagonistic proteins, and the switch DNA. Such an interaction is novel within the biological context of phage switches. However, the network partly resembles a theoretic mixed feedback module able to show bistability. From comparisons between experimental data and model predictions based on mathematical descriptions, it is verified that TP901-1 could be a rst biological example of a phage switch achieving bistability through the trans-acting e ect of a repressing heteromer.
While networks such as that of TP901-1, relies on di usible factors for the maintenance of memory over cell divisions, another way of staying devoted to a distinct state is marking the activity state of a gene on its DNA. In eukaryotes such marks are known, either as methylation of cytosine bases or modi cations of the nucleosomes that wind the DNA into chromatin structures. Once established the patterns may be conserved over many cell generations. The self-sustainable nature of the patterns is attributed to the cis-acting mechanism of read-write enzymes that facilitates the same histone modi cations as they recognize. Developing olfactory neurons become devoted to expression of one version of hundreds of olfactory receptor genes present in the mammalian genome. Ol factory receptor genes are very similar in sequence and upstream promoter regions. This disqualify simple gene regulation by a realistic pool of di usible trans-acting factors as the activation of one receptor gene must result in the continuous repression of the remaining genes. Consequently di erentiation of olfactory neurons presents a rst example of a system that seems to require a local cis-acting gene regulatory mechanism.
A novel model is presented that describe the choice of olfactory receptor by a system of coupled bistable regions. The bistability of each receptor gene is attributed to patterns of similar nucleosome marks, governed by the cis-acting mechanism of read-write enzymes. Genes are coupled by a negative feedback on this mechanism by a global factor given by any active gene. The model allows for a detailed study of a mechanism generating multistability, and shows how single gene expression can be obtained in a family of multiple similar genes all bound by the same regulatory mechanisms.
An example of epigenetic di erentiation is the bistable switch of phage TP901-1, in which the devotion to a distinct state is governed by a small network of trans-acting factors. TP901-1 infects lactococcal bacteria and either exploit the host for the production of new phage leading to the death of the host, or become integrated on the host genome as a non-lethal tag-along during subsequent cell divisions. The switch of the phage, responsible for the dedicated choice, is a small DNA fragment comprising two promoters set back-to-back and their adjacent genes. The gene products work as regulators of the promoters, joining the regulatory loop of the switch. In its lethal path, it is proposed that the switch should implement an interaction between the two antagonistic proteins, and the switch DNA. Such an interaction is novel within the biological context of phage switches. However, the network partly resembles a theoretic mixed feedback module able to show bistability. From comparisons between experimental data and model predictions based on mathematical descriptions, it is verified that TP901-1 could be a rst biological example of a phage switch achieving bistability through the trans-acting e ect of a repressing heteromer.
While networks such as that of TP901-1, relies on di usible factors for the maintenance of memory over cell divisions, another way of staying devoted to a distinct state is marking the activity state of a gene on its DNA. In eukaryotes such marks are known, either as methylation of cytosine bases or modi cations of the nucleosomes that wind the DNA into chromatin structures. Once established the patterns may be conserved over many cell generations. The self-sustainable nature of the patterns is attributed to the cis-acting mechanism of read-write enzymes that facilitates the same histone modi cations as they recognize. Developing olfactory neurons become devoted to expression of one version of hundreds of olfactory receptor genes present in the mammalian genome. Ol factory receptor genes are very similar in sequence and upstream promoter regions. This disqualify simple gene regulation by a realistic pool of di usible trans-acting factors as the activation of one receptor gene must result in the continuous repression of the remaining genes. Consequently di erentiation of olfactory neurons presents a rst example of a system that seems to require a local cis-acting gene regulatory mechanism.
A novel model is presented that describe the choice of olfactory receptor by a system of coupled bistable regions. The bistability of each receptor gene is attributed to patterns of similar nucleosome marks, governed by the cis-acting mechanism of read-write enzymes. Genes are coupled by a negative feedback on this mechanism by a global factor given by any active gene. The model allows for a detailed study of a mechanism generating multistability, and shows how single gene expression can be obtained in a family of multiple similar genes all bound by the same regulatory mechanisms.
| Original language | English |
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| Publisher | The Niels Bohr Institute, Faculty of Science, University of Copenhagen |
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| Number of pages | 143 |
| Publication status | Published - 1 Nov 2012 |