# On Your (Methyl) Mark, Get TET1, Go!

Shradha Mukherjee, Jenny Hsieh

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Shradha Mukherjee, Jenny Hsieh. On Your (Methyl) Mark, Get TET1, Go!. Cell Stem Cell, 2013, 13 (2), pp.133-134. 10.1016/j.stem.2013.07.011. hal-04087519

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<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
the substantial endeavors needed to elucidate some of the extremely complex molecular mechanisms underlying the generation of iPSCs and to considerably increase the efficiency of this process, the findings of Pereira et al. represent an important step toward the individualized generation of hematopoietic (stem) cells.

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On Your (Methyl) Mark, Get TET1, Go!

Shradha Mukherjee<fnref n="1" /> and Jenny Hsieh<fnref n="1" />,<fnref n="1" />*

Tet proteins and DNA demethylation are key regulators of embryonic stem cells, but their roles in develop- ment and tissue stem cells remain unclear. In this issue, **Zhang et al. (2013)** show that Tet1 regulates adult hippocampal neurogenesis by controlling progenitor proliferation, and **Tet1 deficiency** generates defects in learning and memory.

Five decades ago it was first demon- strated that newborn neurons are gener- ated from stem cells in the adult brain throughout life. These newborn neurons then integrate into the existing neuronal circuitry and contribute to learning and memory in the dentate gyrus of the hippo- campus (Göritz and Frisén, 2012). In this issue of *Cell Stem Cell*, Zhang et al. (2013) now describe a new player in this process. Though most of the stem cells in the brain are usually nonproliferating or quiescent, like runners at the starting line of a race, they become activated in cohorts to proliferate, undergo neurogen- esis, and generate newborn neurons (see Figure 1).

Zhang et al. now show that Tet proteins control the decision of neural stem and progenitor cells (NSPCs) to proliferate and undergo neurogenesis. Tet proteins can catalyze the addition of covalent hydroxyl modifications to methylated DNA (hydroxymethylation). DNA methyl hydroxylation is associated with activa- tion of genes and is thought to be a key

intermediate in the demethylation pro- cess. Robust levels of Tet proteins and 5hmC are found in embryonic stem cells and in the adult central nervous system. Recent studies suggest that in embryonic stem cells, Tet1 maintains an active state of gene expression and surprisingly, in combination with Prc2 and Sin3a, main- tains a bivalent or poised gene activation state (Williams et al., 2011; Wu et al., 2011). The biological role of Tet1 and 5hmC, however, remained to be deci- phered in the developing and adult ner- vous system.

Zhang et al. generated both conven- tional knockouts (KO) and conditional knockouts (cKO) of Tet1 in mice to elucidate the role of Tet1 in the central nervous system and surprisingly re- vealed a function for Tet1 in learning and memory. Tet1 KO mice did not show any defects in fertility, growth, or early development, consistent with pre- vious work (Dawlaty et al., 2013). Inter- estingly, Tet1 mutant mice did display defects in spatial learning as well as

short-term memory loss when chal- lenged in the Morris water maze, a sys- tem commonly used to test these abili- ties. Due to the well-described role for hippocampal neurogenesis in learning and memory (Deng et al., 2010), the authors next examined the effects of Tet1 deletion on hippocampal NSPCs in vitro. They observed decreased prolif- eration of NSPCs from Tet1 KO mice, with no obvious change in lineage-spe- cific differentiation.

To understand the requirement for Tet1 in adult hippocampal neurogenesis, the authors next generated Nestin-Cre- ERT2 Tet1 cKO mice. They found that deleting Tet1 specifically in adult NSPCs in vivo decreases their proliferation. Lineage tracing also showed that this loss in proliferation led to a decrease in newly generated neurons. However, the authors did not subject the Tet1 cKO mice to behavioral testing, leaving open the question of whether the observed decrease in proliferation of NSPCs and decreased generation of

<figure><img src="image_2.png" /></figure>

<footnote n="1">¹Department of Molecular Biology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA</footnote>

<footnote>*Correspondence: jenny.hsieh@utsouthwestern.edu</footnote>

<footnote>http://dx.doi.org/10.1016/j.stem.2013.07.011</footnote>
adult-born neurons is re-
sponsible for the learning
and memory deficits ob-
served in conventional Tet1
KO mice.

To gain further mecha-
nistic understanding of
these defects, Zhang et al.
compared gene expression
and DNA methylation pat-
terns between Nestin-GFP
NSPCs derived from WT
and Tet1 KO mice. Com-
paring these data sets iden-

tified thirty-nine genes involved in cell
cycle progression, neural protection,
and mitochondria as both hypermethy-
lated and transcriptionally downregu-
lated in Tet1 KO mice. This shows that
within the NSPCs, 5hmC modifications
are produced in a targeted manner
rather than as a global and nonspecific
regulatory process. One interesting
question for future studies is to deter-
mine how Tet1 is targeted to specific
gene locations.

One surprising finding is that the level
of 5hmC on gene promoters was equal,
rather than decreased, in both WT and
Tet1 KO mice even though DNA methyl-
ation is higher in the latter. This result is
somewhat counterintuitive and brings
forth several questions: is it the position
of hydroxylation, rather than the amount,
that determines the state of CpG
methylation? Or is hydroxylation highly
dynamic (e.g., with a short half-life),
such that analysis of additional time
points may reveal differences in hydrox-

ylation levels between WT and Tet1 KO
NSPCs?

In summary, Zhang et al. provide
strong evidence demonstrating the
importance of DNA hydroxymethylation
in adult hippocampal neurogenesis and
the functional consequences of this
modification in controlling learning and
memory. It will be exciting to discover
how Tet1 hydroxymethylation varies
between quiescent NSPCs, activated
NSPCs, and proliferating transit-ampli-
fying neural progenitors, which are dis-
tinctions the current paper has not
addressed. Tet1 hydroxymethylation
may not only control the transition
between these stem/progenitor cell
stages but may also regulate the transi-
tion between cell cycle phases within
these distinct cell types. Consistently,
Zhang et al. also found that Tet1 hy-
droxymethylation controls the expres-
sion of cell cycle genes. Moreover, Tet
protein activity is dependent on oxygen
and the Kreb cycle's metabolite alpha-

ketoglutarate (Tahiliani et al.,
2009). Taken together, this
suggests the tantalizing pos-
sibility that Tet1 may be a
key sensor coupling cell
cycle progression with meta-
bolism to control the fate of
adult hippocampal NSPCs.
Future studies of Tet1 will
not only contribute to our
mechanistic understanding
of NSPC activation but may
also enhance the ability to
expand these and other

stem cell populations for use in regener-
ative medicine.

<figure><img src="image_3.png" /><figcaption>**Figure 1.** *Tet1 Mediates Hydroxymethylation of DNA and Regulates Gene Expression of Neural Stem Cells*</figcaption></figure>

Increased Tet1 activity signals cohorts of neural stem cells to proliferate and undergo neurogenesis in the adult hippocampus, represented here as NSPCs progressing down the track of differentiation and reaching the finish line as fully differentiated neurons. This mechanism adds another potential layer of regulation to neurogenesis-dependent learning and memory.

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Deng, W., Aimone, J.B., and Gage, F.H. (2010). Nat. Rev. Neurosci. 11, 339–350.

Göritz, C., and Frisén, J. (2012). Cell Stem Cell 10, 657–659.

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