TY - JOUR T1 - Two Active X-chromosomes Modulate the Growth, Pluripotency Exit and DNA Methylation Landscape of Mouse Naive Pluripotent Stem Cells through Different Pathways JF - bioRxiv DO - 10.1101/291450 SP - 291450 AU - Juan Song AU - Adrian Janiszewski AU - Natalie De Geest AU - Lotte Vanheer AU - Irene Talon AU - Taeho Oh AU - Vincent Pasque Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/03/29/291450.abstract N2 - Sex is an increasingly important feature of mouse naive pluripotent stem cells (PSCs), but the regulatory processes involved remain enigmatic. Here, we addressed how sex modulates pluripotency by characterizing the transcriptional state, differentiation dynamics, growth and DNA methylation in female ESCs with heterozygous deletions of Dusp9. Our results show that sex-specific regulation of DNA methylation by Dusp9 can be molecularly uncoupled from the regulation of sex-specific differences in growth, transcription and pluripotency exit. We also addressed how sex modulates pluripotency by characterizing, in male and female cells, the transcriptional state and differentiation dynamics of iPSCs. We found that iPSCs adopt distinct sex-specific transcriptional states, pluripotency exit kinetics and growth properties, which correlate with the presence of two active X chromosomes. Differences in growth and pluripotency exit are not explained by X-linked pluripotency genes. We also examined the open chromatin landscape of embryonic stem cells (ESCs). Epigenomic profiling revealed sex-specific open chromatin landscapes associated with pluripotency and development that underlie key pluripotency and signaling transcription factor binding sites. The differential enrichment of binding sites in sex-specific open chromatin regions provides a molecular link between transcriptional regulators, maintenance of and exit from pluripotency. Our results uncover that different pathways regulate distinct sex-specific differences in PSCs and reveal new molecular insights on sex-specific cellular states. ER -