A continuum reaction-diffusion model for spread of gene silencing in chromosomal inactivation

Abstract

Regulation of gene silencing in large regions of chromosomes is crucial for development and disease progression, and there has been an increasing interest in using it for new therapeutics. One example of massive gene silencing is X chromosome inactivation (XCI), a process essential for dosage compensation of X-linked genes. During XCI, most genes in the X chromosome are inactivated following the transcription of XIST, an X-linked long noncoding RNA. Recent experiments with transgenes showed that the spread of gene silencing can be induced by XIST transcription in cis, but the spread is restricted in space. The mechanism of controlling the spread remains unclear. In this work, we develop a continuum reaction-diffusion model that elucidates chromosomal inactivation through a bistable system governed by a regulatory network for XIST-mediated gene silencing. We find that the spread of XIST can be tuned by known negative feedback loops regulating its synthesis and degradation, and that the spread of gene silencing is controlled by a wave-pinning mechanism in which both global regulation of silencing complex and local variations of histone modifications can play crucial roles. In addition, we integrate the discrete three-dimensional arrangement of the X chromosome and autosomes into this continuous model. We use a 3D chromosome structure inferred from experimental data and our modeling framework to show the spatiotemporal regulation for spread of gene silencing. Our method enables the investigation for the inactivation dynamics of large regions of chromosomes with varying degrees of the spread of gene silencing. Our model provides mechanistic insights that quantitatively relate gene regulatory networks to tunability and stability of chromosomal inactivation. Author SummaryPrecise control of gene expression is a fundamental process in biology and turning off large parts of chromosomes is both common in many species and important for development and diseases. A well-known example of chromosomal scale gene silencing is X chromosome inactivation (XCI), which helps balancing gene activity between sexes. XCI is governed by the production of an RNA called XIST, leading to most genes on one X chromosome being turned off. Experiments have shown that XIST can trigger nearby genes to turn off in natural and engineered contexts, but this effect only spreads to specific regions. The exact mechanism for this limit is not very well understood. In this study, the authors created a mathematical model to explain how XIST spreads and controls gene activity. They found that feedback systems involving XIST regulations and chromatin modifications synergize and determine how far the inactivation spreads, through a process similar to a wave that gets "pinned" in place. They also included the 3D shape of chromosomes in their model to better understand how gene silencing happens over time and space. This model helps to quantitatively describe chromosome inactivation with gene regulatory networks.