An official website of the United States government
All eukaryotic genomes are packaged into basic units of DNA wrapped around histone proteins called nucleosomes. The ability of histones to specify a variety of epigenetic states at defined chromatin domains is essential for cell survival. The most distinctive type of chromatin is found at centromeres, which are marked by the centromere-specific histone H3 variant CENP-A. Many of the factors that regulate CENP-A chromatin have been identified; however, our understanding of the mechanisms of centromeric nucleosome assembly, maintenance, and reorganization remains limited. This review discusses recent insights into these processes and draws parallels between centromeric and noncentromeric chromatin assembly mechanisms.
more »
« less
Retargeting of macroH2A following mitosis to cytogenetic-scale heterochromatic domains
The heritability of chromatin states through cell division is a potential contributor to the epigenetic maintenance of cellular memory of prior states. The macroH2A histone variant has properties of a regulator of epigenetic cell memory, including roles controlling gene silencing and cell differentiation. Its mechanisms of regional genomic targeting and maintenance through cell division are unknown. Here, we combined in vivo imaging with biochemical and genomic approaches to show that human macroH2A is incorporated into chromatin in the G1 phase of the cell cycle following DNA replication. The newly incorporated macroH2A retargets the same large heterochromatic domains where macroH2A was already enriched in the previous cell cycle. It remains heterotypic, targeting individual nucleosomes that do not already contain a macroH2A molecule. The pattern observed resembles that of a new deposition of centromeric histone variants during the cell cycle, indicating mechanistic similarities for macrodomain-scale regulation of epigenetic properties of the cell.
more »
« less
- Award ID(s):
- 1817447
- PAR ID:
- 10097855
- Date Published:
- Journal Name:
- The Journal of Cell Biology
- Volume:
- 218
- Issue:
- 6
- ISSN:
- 0021-9525
- Page Range / eLocation ID:
- 1810 to 1823
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract In the last decade, the interactions among histone modifications and DNA methylation and their effect on the DNA structure, i.e., chromatin state, have been identified as key mediators for the maintenance of cell identity, defined as epigenetic cell memory. In this paper, we determine how the positive feedback loops generated by the auto- and cross-catalysis among repressive modifications affect the temporal duration of the cell identity. To this end, we conduct a stochastic analysis of a recently published chromatin modification circuit considering two limiting behaviors: fast erasure rate of repressive histone modifications or fast erasure rate of DNA methylation. In order to perform this mathematical analysis, we first show that the deterministic model of the system is a singular singularly perturbed (SSP) system and use a model reduction approach for SSP systems to obtain a reduced one-dimensional model. We thus analytically evaluate the reduced system’s stationary probability distribution and the mean switching time between active and repressed chromatin states. We then add a computational study of the original reaction model to validate and extend the analytical findings. Our results show that the absence of DNA methylation reduces the bias of the system’s stationary probability distribution toward the repressed chromatin state and the temporal duration of this state’s memory. In the absence of repressive histone modifications, we also observe that the time needed to reactivate a repressed gene with an activating input is less stochastic, suggesting that repressive histone modifications specifically contribute to the highly variable latency of state reactivation.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
-
Histone variants fine-tune transcription, replication, DNA damage repair, and faithful chromosome segregation. Whether and how nucleosome variants encode unique mechanical properties to their cognate chromatin structures remains elusive. Here, using in silico and in vitro nanoindentation methods, extending to in vivo dissections, we report that histone variant nucleosomes are intrinsically more elastic than their canonical counterparts. Furthermore, binding proteins, which discriminate between histone variant nucleosomes, suppress this innate elasticity and also compact chromatin. Interestingly, when we overexpress the binding proteins in vivo, we also observe increased compaction of chromatin enriched for histone variant nucleosomes, correlating with diminished access. Taken together, these data suggest a plausible link between innate mechanical properties possessed by histone variant nucleosomes, the adaptability of chromatin states in vivo, and the epigenetic plasticity of the underlying locus.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1083/jcb.201811109
