Abstract
Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). While the protein-protein interactions of core pluripotency factors have been identified in mouse ESCs, their interactome in human ESCs (hESCs) has not to date been explored. Here we mapped the OCT4 interactomes in naïve and primed hESCs, revealing extensive connections to mammalian ATP-dependent nucleosome remodeling complexes. In naïve hESCs, OCT4 is associated with both BRG1 and BRM, the two paralog ATPases of the BAF complex. Genome-wide location analyses and genetic studies reveal that these two enzymes cooperate in a functionally redundant manner in the transcriptional regulation of blastocyst-specific genes. In contrast, in primed hESCs, OCT4 cooperates with BRG1 and SOX2 to promote chromatin accessibility at ectodermal genes. This work reveals how a common transcription factor utilizes differential BAF complexes to control distinct transcriptional programs in naïve and primed hESCs.
Highlights
Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs)
In summary, we have generated an interactome of protein–protein interactions around OCT4 in primed human ESCs (hESCs) and reconstructed this interactome under recently devised conditions for naïve human pluripotency
Our results indicate that OCT4 engages in dynamic interactions with ATP-dependent chromatin remodelers in human pluripotent states
Summary
Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). This work reveals how a common transcription factor utilizes differential BAF complexes to control distinct transcriptional programs in naïve and primed hESCs. Pluripotency, the ability of a single cell to give rise to all cell types found in an organism, is a fundamental characteristic of embryonic stem cells (ESCs). While the genome-wide targets of OCT4 have been mapped in both mouse and human ESCs32–35, its physical interactome in hESCs has not to date been explored It remains unclear how OCT4 controls distinct transcriptional programs in human naïve and primed pluripotent states. We captured the dynamic OCT4-centered protein–protein interaction networks (interactomes) under the naïve and primed conditions using affinity purification followed by mass spectrometry (AP-MS) and uncovered extensive associations with ATP-dependent chromatin remodelers. Our work indicates that a switch in OCT4 partner association contributes to the activation of distinct target genes in naïve and primed hESCs and their distinct developmental potential
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