Dosage Sensing, Threshold Responses, and Epigenetic Memory: A Systems Biology Perspective on Random X‐Chromosome Inactivation

Abstract

X‐chromosome inactivation ensures dosage compensation between the sexes in mammals by randomly choosing one out of the two X chromosomes in females for inactivation. This process imposes a plethora of questions: How do cells count their X chromosome number and ensure that exactly one stays active? How do they randomly choose one of two identical X chromosomes for inactivation? And how do they stably maintain this state of monoallelic expression? Here, different regulatory concepts and their plausibility are evaluated in the context of theoretical studies that have investigated threshold behavior, ultrasensitivity, and bistability through mathematical modeling. It is discussed how a twofold difference between a single and a double dose of X‐linked genes might be converted to an all‐or‐nothing response and how mutually exclusive expression can be initiated and maintained. Finally, candidate factors that might mediate the proposed regulatory principles are reviewed.

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

“…2B+C). This observation is in agreement with the prediction of the stochastic model of XCI onset that faster Xist upregulation from one allele will result in preferential X inactivation of that chromosome and could account for the Xce effect in this hybrid context (Monkhorst et al, 2008;Mutzel and Schulz, 2020) . In summary, our allele-specific analysis of Xist expression revealed initial biallelic upregulation, which was then resolved to a monoallelic state with preferential inactivation of the B6 chromosome.…”

“…Since XCI induces differential gene activity at two genetically identical chromosomes in the same nucleus, it is an important model for epigenetic gene regulation. The regulatory principles that allow the two X chromosomes to assume opposing activity states are only starting to be elucidated (Mutzel and Schulz, 2020) .…”

“…While the majority of cells directly upregulate Xist monoallelically, we and others have recently shown that a subset of cells transiently express Xist from both chromosomes in a biallelic manner, which is subsequently converted to a monoallelic state (Mutzel et al, 2019;Sousa et al, 2018) . The current model is thus that Xist is initially upregulated independently on each chromosome in a stochastic fashion and that establishment of a monoallelic state is then ensured through negative feedback regulation (Mutzel and Schulz, 2020) . This feedback is thought to be mediated by silencing of an essential X-linked Xist activator (Lyon, 1971;Monkhorst et al, 2008) .…”

Distal and proximal cis-regulatory elements sense X-chromosomal dosage and developmental state at theXistlocus

“…Xist is an essential developmental regulator, which initiates X-chromosome inactivation (XCI) in females to ensure X-chromosome dosage compensation between the sexes (Brown et al, 1991; Penny et al, 1996). Xist is upregulated during early embryonic development from one out of two X chromosomes in females in an X-dosage dependent manner (Mutzel and Schulz, 2020). It then mediates chromosome-wide gene silencing in cis through successive heterochromatinization (Żylicz and Heard, 2020).…”

A RIF1/KAP1-based toggle switch stabilises the identities of the inactive and active X chromosomes during X inactivation

“…The establishment of in cis, self-reinforcing and mutually exclusive circuits on the two Xist alleles could create the ultrasensitivity required to generate a binary switch-type of control 39 . Key to this model, is the idea that the initial stochastic events will trigger a chain of local, mutually exclusive and self-sustaining events to bookmark both Xi and Xa.…”