This content will become publicly available on June 1, 2024
- NSF-PAR ID:
- 10435084
- Date Published:
- Journal Name:
- Mathematics of Control, Signals, and Systems
- Volume:
- 35
- Issue:
- 2
- ISSN:
- 0932-4194
- Page Range / eLocation ID:
- 399 to 432
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Herrmann, Carl (Ed.)Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit’s constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.more » « less
-
Epigenetic cell memory (ECM), the inheritance of gene expression patterns without changes in genetic sequence, is a critical property of multi-cellular organisms. Chromatin state, as dictated by histone covalent modifications, has recently appeared as a mediator of ECM. In this paper, we conduct a stochastic analysis of the histone modification circuit that controls chromatin state to determine key biological parameters that affect ECM. Specifically, we derive a one-dimensional Markov chain model of the circuit and analytically evaluate both the stationary probability distribution of chromatin state and the mean time to switch between active and repressed chromatin states. We then validate our analytical findings using stochastic simulations of the original higher dimensional circuit reaction model. Our analysis shows that as the speed of basal decay of histone modifications decreases compared to the speed of autocatalysis, the stationary probability distribution becomes bimodal and increasingly concentrated about the active and repressed chromatin states. Accordingly, the switching time between active and repressed chromatin states becomes larger. These results indicate that time scale separation among key constituent processes of the histone modification circuit controls ECM.more » « less
-
Epigenetic cell memory (ECM),the inheritance of gene expression patterns without changes in genetic sequence,is acritical property of multi-cellular organisms.Chromatin state, as dictated by histone covalent modifications, has recently appeared as a mediator of ECM. In this paper,we conduct a stochastic analysis of the histone modification circuit that controls chromatin state to determine key biological parameters that affect ECM. Specifically, we derive a one-dimensional Markov chain model of the circuit and analytically evaluate both the stationary probability distribution of chromatin state and the mean time to switch between active and repressed chromatin states.We then validate our analytical findings using stochastic simulations of the original higher dimen- sional circuit reaction model.Our analysis shows that as the speed of basal decay of histone modifications decreases compared to the speed of autocatalysis,the stationary probability distribution becomes bimodal and increasingly concentrated about the active and repressed chromatin states. Accordingly, the switching time between active and repressed chromatin states becomes larger.These results indicate that timescale separation among key constituent processes of the histone modification circuit controls ECM.more » « less
-
Polycomb Group (PcG) proteins are part of an epigenetic cell memory system that plays essential roles in multicellular development, stem cell biology, X chromosome inactivation, and cancer. In animals, plants, and many fungi, Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to assemble transcriptionally repressed facultative heterochromatin. PRC2 is structurally and functionally conserved in the model fungus
Neurospora crassa , and recent work in this organism has generated insights into PRC2 control and function. To identify components of the facultative heterochromatin pathway, we performed a targeted screen ofNeurospora deletion strains lacking individual ATP-dependent chromatin remodeling enzymes. We found theNeurospora homolog of IMITATION SWITCH (ISW) is critical for normal transcriptional repression, nucleosome organization, and establishment of typical histone methylation patterns in facultative heterochromatin domains. We also found that stable interaction between PRC2 and chromatin depends on ISW. A functional ISW ATPase domain is required for gene repression and normal H3K27 methylation. ISW homologs interact with accessory proteins to form multiple complexes with distinct functions. Using proteomics and molecular approaches, we identified three distinctNeurospora ISW-containing complexes. A triple mutant lacking three ISW accessory factors and disrupting multiple ISW complexes led to widespread up-regulation of PRC2 target genes and altered H3K27 methylation patterns, similar to an ISW-deficient strain. Taken together, our data show that ISW is a key component of the facultative heterochromatin pathway inNeurospora , and that distinct ISW complexes perform an apparently overlapping role to regulate chromatin structure and gene repression at PRC2 target domains. -
Transcriptional gene silencing (TGS) can serve as an innate immunity against invading DNA viruses throughout Eukaryotes. Geminivirus code for TrAP protein to suppress the TGS pathway. Here, we identified an Arabidopsis H3K9me2 histone methyltransferase, Su(var)3-9 homolog 4/Kryptonite (SUVH4/KYP), as a bona fide cellular target of TrAP. TrAP interacts with the catalytic domain of KYP and inhibits its activity in vitro. TrAP elicits developmental anomalies phenocopying several TGS mutants, reduces the repressive H3K9me2 mark and CHH DNA methylation, and reactivates numerous endogenous KYP-repressed loci in vivo. Moreover, KYP binds to the viral chromatin and controls its methylation to combat virus infection. Notably, kyp mutants support systemic infection of TrAP-deficient Geminivirus. We conclude that TrAP attenuates the TGS of the viral chromatin by inhibiting KYP activity to evade host surveillance. These findings provide new insight on the molecular arms race between host antiviral defense and virus counter defense at an epigenetic level.