Regulation of Pluripotency and Self- Renewal of ESCs through Epigenetic- Threshold Modulation and mRNA Pruning

Abstract

SUMMARY ES cell pluripotency requires bivalent epigenetic modifications of key developmental genes regulated by various transcription factors and chromatin modifying enzymes. How these factors coordinate with one another to maintain the bivalent chromatin state so that ES cells can undergo rapid self-renewal while retaining pluripotency is poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and Histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of mRNAs transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA de-capping. These opposing functions of Utf1 promote coordinated differentiation. The mRNA degradation function also ensures rapid cell proliferation by blocking the Myc-Arf feedback control. Thus, Utf1 couples the core pluripotency factors with Myc and PRC2 networks to promote the pluripotency and proliferation of ESCs.

Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis

“…S3). Although the depletion of the remaining 32 genes did not exhibit obvious/consistent self-renewal maintenance defects, we cannot rule out the possibility that at least some of them are essential for ESC differentiation [e.g., Utf1 (36) and Eras (37)] and/or the establishment of the pluripotent state, attributes not assessed by our self-renewal assay.…”

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

“…SOX2 could compete directly with PRC2 for chromatin binding at bivalent domains and/or act indirectly, e.g., through its control of Utf1 expression (60). To our knowledge, this is the first example of a lineage-specific transcription factor that maintains the bivalent state at the promoters of poised genes, thus coordinating the onset of a developmental (neurogenic) program and consequently ensuring a robust and appropriate terminal (neuronal) differentiation process.…”

Transcriptional and epigenetic mechanisms of cellular reprogramming to induced pluripotency

“…Utf1 ensures rapid proliferation of ESCs by mRNA pruningmediated inhibition of Arf expression [79], which might explain why Utf1 markedly enhances the efficiency of iPSC generation even in the absence of c-Myc [80]. Collectively, these results highlight the complex interplay of the OSKM reprogramming factors with regulators of chromatin structure in the establishment and maintenance of a ground pluripotent state.…”

“…transcription factor Utf1, a direct downstream target of Oct4 and Sox2, is strongly enriched on bivalent genes in ESCs, where it tightly controls their poised state by preventing excessive PRC2 binding and promoting the tagging of mRNAs generated from 'leaky' transcription for subsequent cytoplasmic degradation (a process referred to as mRNA pruning) ( Figure 2B) [79]. Utf1 ensures rapid proliferation of ESCs by mRNA pruningmediated inhibition of Arf expression [79], which might explain why Utf1 markedly enhances the efficiency of iPSC generation even in the absence of c-Myc [80].…”