Abstract

BackgroundPrecise gene dosage of the X chromosomes is critical for normal development and cellular function. In mice, XX female somatic cells show transcriptional X chromosome upregulation of their single active X chromosome, while the other X chromosome is inactive. Moreover, the inactive X chromosome is reactivated during development in the inner cell mass and in germ cells through X chromosome reactivation, which can be studied in vitro by reprogramming of somatic cells to pluripotency. How chromatin processes and gene regulatory networks evolved to regulate X chromosome dosage in the somatic state and during X chromosome reactivation remains unclear.ResultsUsing genome-wide approaches, allele-specific ATAC-seq and single-cell RNA-seq, in female embryonic fibroblasts and during reprogramming to pluripotency, we show that chromatin accessibility on the upregulated mammalian active X chromosome is increased compared to autosomes. We further show that increased accessibility on the active X chromosome is erased by reprogramming, accompanied by erasure of transcriptional X chromosome upregulation and the loss of increased transcriptional burst frequency. In addition, we characterize gene regulatory networks during reprogramming and X chromosome reactivation, revealing changes in regulatory states. Our data show that ZFP42/REX1, a pluripotency-associated gene that evolved specifically in placental mammals, targets multiple X-linked genes, suggesting an evolutionary link between ZFP42/REX1, X chromosome reactivation, and pluripotency.ConclusionsOur data reveal the existence of intrinsic compensatory mechanisms that involve modulation of chromatin accessibility to counteract X-to-Autosome gene dosage imbalances caused by evolutionary or in vitro X chromosome loss and X chromosome inactivation in mammalian cells.

Highlights

  • Precise gene dosage of the X chromosomes is critical for normal development and cellular function

  • Our data reveal the existence of intrinsic compensatory mechanisms that involve modulation of chromatin accessibility to counteract X-to-Autosome gene dosage imbalances caused by evolutionary or in vitro X chromosome loss and X chromosome inactivation in mammalian cells

  • The Xa was globally 1.33 times more accessible than the median of all autosomes on the same allele (Fig. 1D, right). These results suggest that a 1.33-fold increase in chromatin accessibility contributes to X chromosome to autosome gene dosage compensation, which is in line with what is observed at the transcriptional level [22]

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Summary

Introduction

Precise gene dosage of the X chromosomes is critical for normal development and cellular function. To balance for X chromosome differences between female XX and male XY cells, placental mammals have evolved a system in which dosage compensation is achieved by random X chromosome inactivation (XCI) of one of the two X chromosomes during early female embryogenesis [10,11,12,13,14]. This way, only one X chromosome is active in both female and male cells. The molecular processes underlying the evolution of XCU in mammals remain unclear

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