Geminin Regulates the Transcriptional and Epigenetic Status of Neuronal Fate-Promoting Genes during Mammalian Neurogenesis

Abstract

Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural basic helix-loop-helix (bHLH) transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. However, maintaining geminin at high levels was not sufficient to prevent terminal neuronal differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis.

Geminin loss causes neural tube defects through disrupted progenitor specification and neuronal differentiation

“…Previously, we demonstrated that Geminin has a role in regulating the epigenetic status, expression, or activity of critical transcription factors during primary neurogenesis in Xenopus and also during in vitro mouse ES cell differentiation towards neuroectoderm (Lim et al, 2011; Seo et al, 2005; Yellajoshyula et al, 2012, 2011). However, analyzing Geminin's in vivo function in mammals was hampered due to the preimplantation lethality of Geminin null embryos (Gonzalez et al, 2006).…”

DNA hypermethylation enhanced telomerase reverse transcriptase expression in human-induced pluripotent stem cells

“…After the ChIP step, the recovered chromatin samples were subjected to qPCR (ChIP-qPCR) using specific primers (Supplemental Table 2). The percent-input values were calculated as described previously [18]. The qPCR data for each primer pair were represented as percent-input by calculating each specific DNA fragment in immunoprecipitates relative to that in input DNA.…”

Licensing of DNA replication, cancer, pluripotency and differentiation: An interlinked world?

“…Antagonism between Geminin and Brg1 has also been proposed to control acquisition of trophoectoderm markers and maintain expression of the core pluripotency genes in mouse embryonic stem (ES) cells [42]. In a recent study by Kroll's group, it was suggested that Geminin antagonizes bHLH transcription factors that promote neurogenesis by maintaining the bivalent status of their promoters [43].…”