ImprintedZac1in neural stem cells

Abstract

Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.

Children Conceived by Assisted Reproductive Technology Prone to Low Birth Weight, Preterm Birth, and Birth Defects: A Cohort Review of More Than 50,000 Live Births During 2011–2017 in Taiwan

“…Exogenous Gonadotropins administered to the ovary during controlled ovarian stimulation causes epigenetic changes in peg1, kcnq1ot1, zac (Zac1), and h19 (25). Zac1 plays an important role in neural stem cell quiescence, proliferation and differentiation (26). Either loss or gain of Zac1 expression was reported to be associated with reduced growth rates and intellectual disability (27), and altered methylation of kcnq1ot1 and h19 was also reported in children with intellectual disability (28).…”

Molecular epigenetic switches in neurodevelopment in health and disease

“…Furthermore, epigenetic “ON or OFF” switches at imprinted genes provide a versatile mechanism for dosage regulation of genes with an important role in balancing stem cell quiescence vs. proliferation. These changes occur in a temporospatial manner through so far incompletely understood mechanism across the genome at several loci (Hoffmann et al, 2014 ; Daniel et al, 2015 ) and may be therefore relabeled as “epigenomic switches”.…”

“…In spite of these varying models, the cellular and molecular mechanisms through which imprinted genes influence neuronal functions remain so far poorly understood. Recent studies on the roles of imprinted genes in NSCs provide, however, new clues to their function and an unexpected flexibility in genomic imprinting (Hoffmann et al, 2014 ; Daniel et al, 2015 ).…”

“…Taken together, these findings exemplify how genomic imprinting can be switched off during confined developmental time windows in specific neuronal cell types and indicate an unprecedented flexibility of this epigenetic mechanism. Transient genomic imprinting in NSCs is not restricted to Dlk1-Dio3 , but has been also suggested to Igf2-H19 and Rasgrf1 in very small embryonic-like stem cells (Hoffmann et al, 2014 ; Daniel et al, 2015 ). Collectively, molecular epigenetic ON and OFF switches at imprinted genes may provide a versatile mechanism for dosage regulation of genes with an important role in balancing stem cell quiescence vs. proliferation.…”

Epigenetic cues modulating the generation of cell‐type diversity in the cerebral cortex

“…Full knockout of Zac1 results in hydrocephaly and decreased brain size, whereas Zac1 overexpression in RGPs triggers premature cell cycle exit because of induction of Cdkn1c expression (Daniel et al . ; Rraklli et al . ).…”