Abstract
Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications.
Highlights
Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states
When embryonic stem cells (ESCs) differentiate into a given lineage, active histone marks are maintained in genes that are expressed in that specific lineage, while the repressive histone marks in those genes are concomitantly removed[16]
Pluripotent-related genes (e.g. Prdm[14], Rex[1] and Lefty1) were dysregulated uniquely in Dnmt[1] KO ESCs, while Uhrf[1] KO cells exhibited dysregulation in several developmental genes (Hand[1] and Sox15), and genes exclusively expressed at the early embryonic stage (e.g. Klf[2] and Zscan4b) (Fig. 1b)
Summary
Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Uhrf[1] is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt[1] and in heterochromatin formation alongside G9a, Trim[28], and HDACs. Uhrf[1] is not essential in ESC self-renewal, it remains elusive how Uhrf[1] regulates cell specification. Uhrf[1] (Ubiquitin-like, with PHD and RING finger domains 1, known as NP95 or ICBP90) is a multi-domain nuclear protein that faithfully regulates epigenetic modifications through two mechanisms: (i) by recognition of histone marks through subsequent interactions with chromatin modifying proteins and (ii) DNA methylation maintenance[1]. Metazoans have three subsets of this complex: the Set1/ COMPASS, trithorax (Trx), and trithorax-related (Trr) These complexes share the same core protein components, but differ in their catalytic subunits. In spite of overwhelming evidence that Uhrf[1] regulates repressive histone marks, it is still unclear whether Uhrf[1] is involved in the regulation of active chromatin marks
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