UHRF1 Licensed Self-Renewal of Active Adult Neural Stem Cells

Abstract

Adult neurogenesis in the brain continuously seeds new neurons throughout life, but how homeostasis of adult neural stem cells (NSCs) is maintained is incompletely understood. Here, we demonstrate that the DNA methylation adapter ubiquitin-like, containing PHD and RING finger domains-1 (UHRF1) is expressed in, and regulates proliferation of, the active but not quiescent pool of adult neural progenitor cells. Mice with a neural stem cell-specific deficiency in UHRF1 exhibit a massive depletion of neurogenesis resulting in a collapse of formation of new neurons. In the absence of UHRF1, NSCs unexpectedly remain in the cell cycle but with a 17-fold increased cell cycle length due to a failure of replication phase entry caused by promoter demethylation and derepression of Cdkn1a, which encodes the cyclin-dependent kinase inhibitor p21. UHRF1 does not affect the proportion progenitor cells active within the cell cycle but among these cells, UHRF1 is critical for licensing replication re-entry. Therefore, this study shows that a UHRF1-Cdkn1a axis is essential for the control of stem cell self-renewal and neurogenesis in the adult brain. Stem Cells 2018;36:1736-1751.

In silicoAPC/C substrate discovery reveals cell cycle degradation of chromatin regulators including UHRF1

“…Since many APC/C substrates are linked to proliferative control, we examined the contribution of UHRF1, and its degradation by APC/C, to cell cycle. Consistent with prior reports, UHRF1 depletion increased the fraction of cells in G1-phase ((65); data not shown). To further investigate the role of UHRF1 in cell cycle, we examined mitotic cells following UHRF1 depletion.…”

Investigating the Relationship Between Neuronal Cell Death and Early DNA Methylation After Ischemic Injury

“…UHRF1 is highly expressed in cancer cells, and it is thought that its level is correlated with the ability of cancer cells to proliferate (Ashraf et al, 2017). As accumulating evidences indicated that UHRF1 is also related to the S phase entry in normal cells (Bonapace et al, 2002;Blanchart et al, 2018), UHRF1 has been thought to play a role in cell proliferation. Therefore, up-regulation of UHRF1 mRNA seen in our in vivo results might be related to the level of DNA methylation in dividing cells such as glial and endothelial cells in the brain under ischemic conditions.…”

Functional and Pathological Roles of AHCY

“…DNA methyltransferase 1 (DNMT1), the enzyme responsible for the maintenance of DNA methylation, recognizes hemimethylated DNA during replication and establishes the methyl group in the newly synthesized DNA (Bonasio et al, 2010). This process is assisted by several accessory proteins, including the multidomain protein UHRF1 (Blanchart et al, 2018). In a proteomic survey during the cell cycle of HeLa cells, AHCY was found as a partner of DNMT1 (Ponnaluri et al, 2018) (Figure 2).…”