Computational modeling reveals cell-cycle dependent kinetics of H4K20 methylation states during Xenopus embryogenesis

Abstract

SUMMARYHistone modifications regulate chromatin architecture and thereby control gene expression. Rapid cell divisions and DNA replication however lead to a dilution of histone modifications and can thus affect chromatin mediated gene regulation So how does the cell-cycle shape the histone modification landscape, in particular during embryogenesis when a fast and precise control of cell-specific gene expression is required?We addressed this question in vivo by manipulating the cell-cycle during early Xenopus laevis embryogenesis. The global distribution of un-, mono- di- and tri-methylated histone H4K20 was measured by mass spectrometry in normal and cell-cycle arrested embryos over time. Using multi-start maximum likelihood optimization and quantitative model selection, we found that three specific methylation rate constants were required to explain the measured H4K20 methylation state kinetics. Interestingly, demethylation was found to be redundant in the cycling embryos but essential in the cell-cycle arrested embryos.Together, we present the first quantitative analysis of in vivo histone H4K20 methylation kinetics. Our computational model shows that demethylation is only essential for regulating H4K20 methylation kinetics in non-cycling cells. In rapidly dividing cells of early embryos, we predict that demethylation is dispensable, suggesting that cell-cycle mediated dilution of chromatin marks is an essential regulatory component for shaping the epigenetic landscape during early embryonic development.

Efficient computation of adjoint sensitivities at steady-state in ODE models of biochemical reaction networks

“…The computation time of these methods is usually dominated by the computation time required for the evaluation of the objective function gradient. For the objective function (7), the gradient is given by…”

“…Ordinary differential equation (ODE) models are widely used to describe the dynamics of biochemical processes such as signalling [1][2][3], metabolism [4,5] or gene regulation [6,7]. These models can capture the mechanistic details of interactions between biochemical species, aggregate current knowledge and integrate heterogeneous data types.…”

Histone Modifications in Stem Cell Development and Their Clinical Implications

“…In recent publications, computational modeling approaches have been used to investigate and model the role of the modification kinetics in setting up specific chromosomal domains and conferring epigenetic plasticity ( Alabert et al., 2020 ; Schuh et al., 2020 ). Two aspects common to the modeling approaches are: (1) the existence of potentially competing modifications, such as H3K4me (active) and H3K9me (inactive) or H3K27me (inactive) and H3K36me (active), and (2) a low contribution of cell-cycle-mediated modification dilution to the total modification profile.…”