Forged byDXZ4,FIRRE, andICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome

Recent efforts in mapping spatial genome organization have revealed three evocative and conserved structural features of the inactive X in female mammals. First, the chromosomal conformation of the inactive X reveals a loss of topologically associated domains (TADs) present on the active X. Second, the macrosatelliteDXZ4emerges as a singular boundary that suppresses physical interactions between two large TAD-depleted megadomains. Third,DXZ4reaches across several megabases to form superloops with two other X-linked tandem repeats,FIRREandICCE, which also loop to each other. Although all three structural features are conserved across rodents and primates, deletion of mouse and human orthologs ofDXZ4andFIRREfrom the inactive X have revealed limited impact on X chromosome inactivation (XCI) and escapein vitro.In contrast, loss ofXistor SMCHD1 have been shown to impair TAD erasure and gene silencing on the inactive X. In this perspective, we summarize these results in the context of new research describing disruption of X-linked tandem repeatsin vivo, and discuss their possible molecular roles through the lens of evolutionary conservation and clinical genetics. As a null hypothesis, we consider whether the conservation of some structural features on the inactive X may reflect selection for X-linked tandem repeats on account of necessarycis- andtrans-regulatory roles they may play on the active X, rather than the inactive X. Additional hypotheses invoking a role for X-linked tandem repeats on X reactivation, for example in the germline or totipotency, remain to be assessed in multiple developmental models spanning mammalian evolution.