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

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.