Transient pairing of homologous Oct4 alleles accompanies the onset of embryonic stem cell differentiation.

The relationship between chromatin organization and transcriptional regulation is an area of intense investigation. We characterized the spatial relationships between alleles of the Oct4, Sox2, and Nanog genes in single cells during the earliest stages of mouse embryonic stem cell (ESC) differentiation and during embryonic development. We describe homologous pairing of the Oct4 alleles during ESC differentiation and embryogenesis, and we present evidence that pairing is correlated with the kinetics of ESC differentiation. Importantly, we identify critical DNA elements within the Oct4 promoter/enhancer region that mediate pairing of Oct4 alleles. Finally, we show that mutation of OCT4/SOX2 binding sites within this region abolishes inter-chromosomal interactions and affects accumulation of the repressive H3K9me2 modification at the Oct4 enhancer. Our findings demonstrate that chromatin organization and transcriptional programs are intimately connected in ESCs and that the dynamic positioning of the Oct4 alleles is associated with the transition from pluripotency to lineage specification.

Hogan MS ，Parfitt DE ，Zepeda-Mendoza CJ ，Shen MM ，Spector DL ... -  《-》

Chromosome togetherness at the onset of ESC differentiation.

Pairing of homologous alleles is a phenomenon generally associated with imprinted and mono-allelically expressed loci. In this issue, Hogan et al. (2015) examine the earliest steps between pluripotency and lineage commitment in ESCs and find a critical role for transient pairing of Oct4 alleles in exiting the pluripotent state.

Krivega I ，Dean A 《-》

Esrrb activates Oct4 transcription and sustains self-renewal and pluripotency in embryonic stem cells.

Zhang X ，Zhang J ，Wang T ，Esteban MA ，Pei D ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》

Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells.

Nanog, Oct4, and Sox2 are the core regulators of mouse (m)ESC pluripotency. Although their basic importance in human (h)ESCs has been demonstrated, the mechanistic functions are not well defined. Here, we identify general and cell-line-specific requirements for NANOG, OCT4, and SOX2 in hESCs. We show that OCT4 regulates, and interacts with, the BMP4 pathway to specify four developmental fates. High levels of OCT4 enable self-renewal in the absence of BMP4 but specify mesendoderm in the presence of BMP4. Low levels of OCT4 induce embryonic ectoderm differentiation in the absence of BMP4 but specify extraembryonic lineages in the presence of BMP4. NANOG represses embryonic ectoderm differentiation but has little effect on other lineages, whereas SOX2 and SOX3 are redundant and repress mesendoderm differentiation. Thus, instead of being panrepressors of differentiation, each factor controls specific cell fates. Our study revises the view of how self-renewal is orchestrated in hESCs.

Wang Z ，Oron E ，Nelson B ，Razis S ，Ivanova N ... -  《-》

Role of SOX2 in maintaining pluripotency of human embryonic stem cells.

Adachi K ，Suemori H ，Yasuda SY ，Nakatsuji N ，Kawase E ... -  《-》