Dosage compensation articles from across Nature Portfolio

Through a CRISPR-activation screen, Ravid Lustig et al. show that GATA transcription factors activate long-range Xist enhancers to upregulate Xist expression and initiate X chromosome inactivation in early mouse embryos.

A newly identified gene, sex chromosome activation (SOA), is a master regulator of dosage compensation in Anopheles gambiae.

Here the authors reveal that a neomorphic mutation in chromatin protein SMCHD1 enhances SMCHD1-mediated gene silencing, including at the FSHD disease-relevant locus, while depleting SMCHD1-mediated chromatin interactions, suggesting these SMCHD1 functions are unlinked.

Here, the authors show that transcripts arising from the X chromosome are less decorated by m⁶A and are more stable than their autosomal counterparts. Consistently, acute depletion of m⁶A preferentially stabilizes autosomal transcripts and thus results in aberrant dosage compensation.

Polycomb repressive complexes 1 and 2 both regulate maintenance of X inactivation in extra-embryonic lineages of post-implantation embryos by affecting overlapping yet different genes, thus implying potentially independent roles for the two complexes.

Here the authors investigate the functional relevance of X-chromosome inactivation (XCI) regulator Xist in hematopoiesis. They find that Xist loss leads to changes in the ratio of hematopoietic progenitor cells and results in chromatin accessibility and transcriptional upregulation on the inactive X chromosome, including XCI escape genes known to be associated with cell cycle and immune response.

Inactivation of one of the two female X chromosomes involves condensing it into a repressive subnuclear territory, which is depleted of transcriptional components and undergoes late-stage DNA replication. Two new studies unravel how compartmentalization of the inactive mammalian X chromosome affects transcription and DNA replication.

Unlike autosomal genes, X-linked genes are expressed from only one copy in both male and female mammals. How cells increase X-linked gene expression to match autosomal levels is unclear. New evidence suggests that lower levels of RNA modifications on X chromosome-derived transcripts critically regulate mRNA stability and help to balance X-to-autosome gene expression levels.

The molecular mechanisms by which a few molecules of the long non-coding RNA Xist silence genes on the entire X chromosome are poorly understood. New evidence suggests that dimeric foci of Xist seed the formation of large protein assemblies that contain a wide spectrum of proteins, such as SPEN (SHARP), CIZ1, CELF, PTBP1 and components of Polycomb repressive complexes 1 and 2. These assemblies, each of which may contain hundreds to thousands of molecules of proteins, extend spatially beyond each focus of Xist, which explains how this long non-coding RNA triggers silencing across an entire chromosome.

Upregulation of the X chromosome compensates for the presence of a single active X chromosome in mammals, but this has been difficult to measure and to understand mechanistically. A study now demonstrates that increased burst frequency boosts the transcriptional output of X-linked genes in male and female cells with a single active X chromosome. Interestingly, female embryonic stem cells lack increased burst frequency, which is established only after inactivation of the X chromosome takes place; this finding reveals a switch that can modulate transcriptional bursting.

The long non-coding RNA Xist induces heterochromatinization of the X chromosome by recruiting repressive protein complexes to chromatin. Here we gather evidence, from the literature and from computational analyses, showing that Xist assemblies are similar in size, shape and composition to phase-separated condensates, such as paraspeckles and stress granules. Given the progressive sequestration of Xist’s binding partners during X-chromosome inactivation, we formulate the hypothesis that Xist uses phase separation to perform its function.