Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration

Abstract

In order to understand whether early epigenetic mechanisms instruct the long-term behavior of neural stem cells (NSCs) and their progeny, we examined Uhrf1 (ubiquitin-like PHD ring finger-1; also known as Np95), as it is highly expressed in NSCs of the developing brain and rapidly down-regulated upon differentiation. Conditional deletion of Uhrf1 in the developing cerebral cortex resulted in rather normal proliferation and neurogenesis but severe postnatal neurodegeneration. During development, deletion of Uhrf1 lead to global DNA hypomethylation with a strong activation of the intracisternal A particle (IAP) family of endogenous retroviral elements, accompanied by an increase in 5-hydroxymethylcytosine. Down-regulation of Tet enzymes rescued the IAP activation in Uhrf1 conditional knockout (cKO) cells, suggesting an antagonistic interplay between Uhrf1 and Tet on IAP regulation. As IAP up-regulation persists into postnatal stages in the Uhrf1 cKO mice, our data show the lack of means to repress IAPs in differentiating neurons that normally never express Uhrf1. The high load of viral proteins and other transcriptional deregulation ultimately led to postnatal neurodegeneration. Taken together, these data show that early developmental NSC factors can have long-term effects in neuronal differentiation and survival. Moreover, they highlight how specific the consequences of widespread changes in DNA methylation are for certain classes of retroviral elements. Neurogenesis is a complex process comprising several critical steps from proliferation of stem and progenitor cells to their differentiation and maturation into neurons. Each step of the neurogenic cascade is under tight transcriptional and post-transcriptional control and needs to be coordinated with the next differentiation step. Several transcription factors have been identified with key roles in specifying neurogenic fate in neural stem or progenitor cells, such as proneural factors Ascl1 and Ngn2, homeobox transcription factors Pax6 and Dlx, and many others (Schuurmans and Guillemot 2002;Wilkinson et al. 2013). These factors have early effects on neural stem cell (NSC) behavior and neurogenesis via transcriptional regulation. However, much less is known regarding whether and how mechanisms acting early in NSCs may exert effects only at later stages of neuronal differentiation or on postnatal gliogenesis. One of the key questions lies in unraveling the extent to which factors present at early developmental stages leave long-lasting traces on transcriptional regulation, affecting late stages of neuronal differentiation.One mechanism by which gene regulation is modulated is via epigenetic modifications, such as DNA methylation (Tyssowski et al. 2014). DNA methylation is carried out by the Dnmt group of methyltransferases: Dnmt1, Dnmt3a, and Dnmt3b. Dnmt3 enzymes are de novo methyltransferases, whereas Dnmt1 is largely involved in maintaining DNA methylation in somatic cycling cells. DNA methylation modulates the expression of

UHRF1-repressed 5’-hydroxymethylcytosine is essential for the male meiotic prophase I

“…However, we found downregulation of DNA methylation here had little effect on gene transcription increase. A similar conclusion is also reported elsewhere 34,72 . So we think the mechanism of UHRF1 regulating gene transcription in meiosis is different from that in spermatogonium differentiation.…”

“…They also pointed out that the DNA methylation might regulate directly or indirectly the genes guiding spermatogonial differentiation (for example, Plzf and Kit) 23 . One of the key player of DNA methylation is UHRF1, a multifunctional protein [24][25][26] , which is essential for maintenance or de novo DNA methylation [27][28][29][30][31][32][33][34] . However, the role of UHRF1 in male germ cells after the spermatogonia differentiation, for example, meiosis, remains largely unknown.…”

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

“…Alterations in RE expression activity the dnmt1 -/-CMZ (Figures 7,8) are exciting given Dnmt1's known roles in repressing RE activity [36][37][38][39] . RE expression was aberrant in most dnmt1 -/-CMZs examined (Figure 7); however, expression changes and levels were variable between larvae, suggesting that the location and extent of genomic hypomethylation resulting from loss of dnmt1 function is inherently variable between cells of each larva.…”

Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

“…Indeed, among our top meta-analysis results (FDR<0.05), we found that the canonical Marker of Proliferation Ki-67 (Mki67) was more highly expressed in bLRs in adulthood, similar to the upregulation observed histologically in development in earlier generations (16) and potentially in adulthood (11, 108). bLRs also exhibited greater expression of ubiquitin-like PHD ring finger-1 (Uhrf1), a regulator of methylation and promoter of cell survival that is highly expressed in neural stem cells and rapidly down-regulated following differentiation (109). These findings confirm that, at least within our model, the relationship between internalizing behavior and cell proliferation is unlikely to be as simple as a general stunting of growth-related processes, as might be hypothesized based on the neurotrophic model of stress-related mood disorders (110).…”