Concise Review: Geminin—A Tale of Two Tails: DNA Replication and Transcriptional/Epigenetic Regulation in Stem Cells

Abstract

Molecular mechanisms governing maintenance, commitment, and differentiation of stem cells are largely unexploited. Molecules involved in the regulation of multiple cellular processes are of particular importance for stem cell physiology, as they integrate different signals and coordinate cellular decisions related with self-renewal and fate determination. Geminin has emerged as a critical factor in DNA replication and stem cell differentiation in different stem cell populations. Its inhibitory interaction with Cdt1, a member of the prereplicative complex, ensures the controlled timing of DNA replication and, consequently, genomic stability in actively proliferating cells. In embryonic as well as somatic stem cells, Geminin has been shown to interact with transcription factors and epigenetic regulators to drive gene expression programs and ultimately guide cell fate decisions. An ever-growing number of studies suggests that these interactions of Geminin and proteins regulating transcription are conserved among metazoans. Interactions between Geminin and proteins modifying the epigenome, such as members of the repressive Polycomb group and the SWI/SNF proteins of the permissive Trithorax, have long been established. The complexity of these interactions, however, is only just beginning to unravel, revealing key roles on maintaining stem cell self-renewal and fate specification. In this review, we summarize current knowledge and give new perspectives for the role of Geminin on transcriptional and epigenetic regulation, alongside with its regulatory activity in DNA replication and their implication in the regulation of stem and progenitor cell biology. STEM CELLS 2017;35:299-310 SIGNIFICANCE STATEMENTThe review focuses on the roles of Geminin in embryonic and somatic stem cells. More specifically, we have addressed how Geminin, through its regulatory roles in transcriptional and epigenetic control, impacts stem cell self-renewal versus differentiation decisions. In recent years, we and other researchers have studied extensively the transcriptional programs affected by Geminin in various developmental stages and tissues using murine models. However, what we wish to emphasize in this review-as well as to summarize findings in order to aid future studies-is the network of proteins that Geminin associates with at the epigenomic level. These interactions are critical for cellular pluri/multi-potency and differentiation decisions of stem and progenitor cells for maintenance of homeostasis. Last, but not least, we provide links between the transcriptional/epigenetic roles of Geminin and its more traditional role as a regulator of DNA replication. We believe that these two otherwise distinct roles of this protein are interconnected and we anticipate that our views will stimulate future studies with cutting edge research investing into how Geminin could be fine-tuned to assist tissue engineering in medical applications.

GemC1 is a critical switch for neural stem cell generation in the postnatal brain

“…Based on earlier analysis, this mutant is expected to show altered ability to form homo and heterodimers with the Geminin family members (Caillat et al, ). It was previously shown that GemC1 forms heterodimers with McIdas and Geminin, whereas Geminin acts antagonistically to GemC1 in the regulation of transcriptional activation of key transcription factors for multiciliogenesis (Arbi et al, ; Caillat et al, ; Caillat et al, ; Kyrousi et al, ; Patmanidi et al, ; Terré et al, ). As Geminin was previously shown to be implicated in stem cell self‐renewal and differentiating decisions (Karamitros et al, ; Spella et al, ), antagonistic roles for Geminin and GemC1 in determining the ependymal cell lineage are likely.…”

How a radial glial cell decides to become a multiciliated ependymal cell

“…Recent findings from our laboratory, describing the role of two novel molecules McIdas and GemC1/Lynkeas, unravel early events of the molecular pathway governing fate commitment decisions of RGCs to ependymal lineage (Kyrousi et al, 2015. McIdas and GemC1/Lynkeas are coiled-coil proteins which are implicated in cell cycle regulation (Balestrini et al, 2010;Caillat et al, 2015;Pefani et al, 2011) and share homology with Geminin, a protein with a dual role in cell cycle progression and cell differentiation [reviewed in Patmanidi et al (2016)]. More specifically, GemC1/Lynkeas is a key molecule regulating DNA replication via binding to TopBP1 and Cdc45 in order to mediate pre-initiation complex formation (Balestrini et al, 2010), while McIdas controls cell cycle progression through its interaction with Geminin (Caillat et al, 2013;Pefani et al, 2011).…”

Lysophosphatidic Acid-induced EGFR Transactivation Promotes Gastric Cancer DNA Replication Through Up-Regulation of Geminin

“…Geminin is a multi-functional protein, which plays pivotal roles in both DNA replication and transcriptional/epigenetic regulation [9]. Moreover, dysregulation of geminin is often found in various types of human cancers.…”