Posts Tagged ‘neural stem cells’

Remyelination of axon requires Gli1 inhibition

Larry H. Bernstein, MD, FCAP, Curator



Inhibition of Gli1 Enhances Remyelination Abilities of Endogenous Stem Cell Populations




If myelin is damaged, the speed of nerve impulse transmission slows substantially. Multiple sclerosis is one example of a disease that causes systematic loss of the myelin sheath. Inflammatory demyelinating diseases also cause progressive damage and loss of the myelin sheath. Regenerating the myelin sheath in these patients is one of the goals of regenerative medicine.

A good deal of data tells us that endogenous remyelination does occur. Unfortunately, this process is overwhelmed by the degree of demyelination in these diseases. A stem cell population called the parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells in the brain are known to remyelinate demyelinated axons.

The Salzer laboratory at the New York Neuroscience Institute examined the ability of a specific adult neural stem cell population to remyelinate axons. These stem cells expressed the transcription factor Gli1.

Salzer and his team showed that this subventricular zone-specific group of neural stem cells were efficiently recruited to demyelinated portions of the brain. This same neural stem cell population was never observed entering healthy axon tracts. This finding shows that these cells seem to specialize in making new myelin sheaths for damaged axon tracts.

Since these neural stem cells expressed Gli1, and since there are drugs that can inhibit Gli1 activity, Salzer’s group wanted to show that Gli1 was a necessary factor for neural stem cell activity. Surprisingly, differentiation of these neural stem cells into oligodendrocytes (which make myelin and remyelinate axons) is significantly enhanced by inhibition of Gli1.

A specific signaling pathway called the hedgehog pathway is known to activate Gli1 and other members of the Gli gene family. However, when the hedgehog pathway in these neural stem cells was completely inhibited, it did not have the same effect and Gli1 inhibition. This suggests that Gli1 is doing more than responding to the hedgehog pathway in these neural stem cells.

Salzer and his colleagues showed that Gli1 inhibition improved myelin deposition in an animal model of experimental autoimmune encephalomyelitis; an inflammatory demyelination disease. Thus, inhibition of Gli1 activity in this preclinical model system increase regeneration of the myelin sheath in demyelinated neurons.

This work elegantly showed that endogenous neural stem cells that can remyelinate axons are present and can be activated by inhibiting Gli1. Furthermore, this activation will nicely enhance the therapeutic capacity of these endogenous cells. This potentially identifies a new therapeutic avenue for the treatment of demyelinating disorders.

This work was published in Nature. 2015 Oct 15;526(7573):448-52. doi: 10.1038/nature14957.


Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination
Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination.

 Nature. 2015 Oct 15;526(7573):448-52.   Epub 2015 Sep 30.

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.



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Neural stem cells aging

Larry H. Bernstein, MD, FCAP, Curator



Aging Stem Cells Provide Clues into Tumor Development

With the enzyme Eyeless knocked out, cells over-proliferate (shown in green) in a fruit fly’s larval brain during reactivated Notch signaling. [University of Oregon]

Investigators at the University of Oregon (UO) have recently uncovered molecular events experienced by stem cells as they age, which could provide new avenues toward the discovery of novel therapies for cancer and neurological disorders. The researchers noticed that these changes arise in Drosophila during the development of the central nervous and at that time a specific protein is expressed, blocking tumor formation.

The UO researchers were focused on the larval stage of fruit fly development, as this is when stem cells generate most of the neurons that form the adult’s brain. During this process the stem cells are rapidly dividing in order to populate the central nervous system of the fly, and they rely heavily on the Notch signaling pathway—a developmentally important signal transduction pathway that has also been linked to cancer.

In previous studies, scientists have described scenarios where Notch signaling ran efficiently and stem cells produce neurons that populate the adult central nervous system. However, with too much Notch, stem cells lose control and over-proliferate—forming large tumors. In humans, adult T-cell leukemia is tied to overactive Notch signaling.

“Stem cells have a really tough job because they have to divide to make the millions of neurons in our brain,” explained Howard Hughes Medical Institute Investigator and senior author Chris Doe, Ph.D., professor of biology at the UO. “If they don’t divide enough, it results in microcephaly or other small brain diseases, but if they divide too much, they make tumors. They have to stay right on that boundary of dividing to make neurons but not dividing excessively and forming a tumor. It’s really walking a tightrope.”

The findings from this study were published recently in Current Biology through an article entitled “Aging Neural Progenitors Lose Competence to Respond to Mitogenic Notch Signaling.”

In the current study, the scientists discovered that if they waited for stem cells to divide a few times and age a bit, they quit responding to Notch. Moreover, the stem cells could not be pushed by high doses of Notch signaling to form tumors.

As the UO researchers looked closer, they uncovered a host of age-related molecular changes. As the stem cells get older and around the same time they begin to resist tumor formation, the stem cells begin expressing a transcription factor protein, known as Eyeless in Drosophila and Pax6 in humans. Its presence blocks Notch signaling.

Dr. Doe and his team described the genetic knockout of Eyeless in these stem cells, which led Notch signaling to overwhelm the precise growth balance and form tumors within the fruit flies.

“If we can identify the stem cells that are relied upon during development, maybe we could find a way to use them later to recreate conditions that might be therapeutic,” noted Dylan Farnsworth, a doctoral candidate at the UO. “If you do it incorrectly, you risk over-proliferation and the development of masses—and cancer.”

“This paper shows that Eyeless is important for winding down the lifespan of the stem cells that are giving rise to the adult brain,” Dr. Doe added. “It’s a stop signal that says it is time to cease responding to Notch signals.”

The UO researchers were excited by their findings and believe that with more extensive research, their system could provide a roadmap for fine-tuning the timing of stem cell-based therapies to restart healthy activity in adult stem cells.


Aging Neural Progenitors Lose Competence to Respond to Mitogenic Notch Signaling

Dylan R. Farnsworth, Omer Ali Bayraktar, and Chris Q. Doe
Cell 7 Dec 2015; 25(23):3058–3068  DOI:


  • Aging INPs lose competence to respond to constitutively active Notch signaling
  • The late temporal factor Eyeless blocks Notch-induced target gene expression
  • Eyeless blocks Notch-induced INP tumor formation


Drosophila neural stem cells (neuroblasts) are a powerful model system for investigating stem cell self-renewal, specification of temporal identity, and progressive restriction in competence. Notch signaling is a conserved cue that is an important determinant of cell fate in many contexts across animal development; for example, mammalian T cell differentiation in the thymus and neuroblast specification in Drosophila are both regulated by Notch signaling. However, Notch also functions as a mitogen, and constitutive Notch signaling potentiates T cell leukemia as well as Drosophila neuroblast tumors. While the role of Notch signaling has been studied in these and other cell types, it remains unclear how stem cells and progenitors change competence to respond to Notch over time. Notch is required in type II neuroblasts for normal development of their transit amplifying progeny, intermediate neural progenitors (INPs). Here, we find that aging INPs lose competence to respond to constitutively active Notch signaling. Moreover, we show that reducing the levels of the old INP temporal transcription factor Eyeless/Pax6 allows Notch signaling to promote the de-differentiation of INP progeny into ectopic INPs, thereby creating a proliferative mass of ectopic progenitors in the brain. These findings provide a new system for studying progenitor competence and identify a novel role for the conserved transcription factor Eyeless/Pax6 in blocking Notch signaling during development.

Supplemental Information

Figure S1, related to Figure 1. Notchintra is nuclear and at qualitatively similar levels when expressed in young or old INP lineages. (A-C’) R9D11-gal4, R16B06-gal and OK107-gal4 driving UAS-Notchintra result in efficient Notchintra protein expression, as visualized by antibody staining. Yellow dashed outlines show INP lineages in central brain labeled by each driver. Scale bar = 10 µm

Figure S2, related to Figure 3. R16B06-gal4 labels old INPs in third instar larval brains. (A) Expression pattern of R16B06-gal4 in both brain lobes of third instar larva. R9D11-gal4 marks young INPs and is shown for comparison. (B-B’’) High magnification images show Dpn+ INPs distal to their parental Type II NB (white dashed line) are labeled by R16B06-gal4. Arrow indicates direction of age progression in lineage. (C-C’’’) Distal INPs (yellow dashed line) labeled by R16B06-gal4 express the old INP specific transcription factor Eyeless (Ey) but not the young INP specific transcription factor Dichaete (D). Images are a single, one micron plane. All panels show third instar larvae; scale bar = 10 µm

Figure S3, related to Figure 7. Notchintra signaling can induce expression of the Notch response element reporter (NRE-PGR) in old INPs but not in GMCs. (A) In wild type, the NRE reporter is expressed at high levels in Type II neuroblasts (arrowhead) and shows progressively weaker levels in the progeny. There are low levels in old INPs (dashed yellow outline; identified by Ey expression), but is not detectable in Prospero (Pros)+ GMCs (arrow). (B) Expression of Notchintra in the old INPs and their progeny using R16B06-gal4 results in elevated expression of the NRE reporter (dashed yellow outline; compare to level in adjacent cells); only Dpn+ INPs show elevated levels of the reporter, Prospero (Pros)+ GMCs show no detectable expression. (C-C’’’) The Notch target E(spl)mγ is expressed in both young and old INPs. (C) Young INPs expressing Dichaete (small white circles) and (C’) old INPs expressing Eyeless (small dashed yellow circles) are positive for Deadpan and the Notch target E(spl)mγ- GFP fusion reporter. Asterisk marks Type II NB, arrow indicates direction of lineage from young to old. All panels show third instar larvae; scale bar = 10 µm.

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Writer and curator: Larry H. Bernstein, MD, FCAP and
Curator: Aviva Lev-Ari, PhD, RN

There is an explosion of work-in-progress in applications to regenerative medicine using inducible pluripotent stem cells in both endothelial and cardiomyocyte postischemic repair, and also in post bone marrow radiation restoration, with benefits and hazards.  The following article is quite novel in that it deals with stem cell regulation by DNA methylation.  Therefore, it deals with the essentiality of methylation of DNA in epigenetic regulation.

This is the fourth discussion of a several part series leading from the genome, to protein synthesis (1), posttranslational modification of proteins (2), examples of protein effects on metabolism and signaling pathways (3), and leading to disruption of signaling pathways in disease (4), and effects leading to mutagenesis.

1.  A Primer on DNAand DNA Replication

2.  Overview of translational medicine

3.  Genes, proteomes, and their interaction

4. Regulation of somatic stem cell Function

5.  Proteomics – The Pathway to Understanding and Decision-making in Medicine

6.  Genomics, Proteomics and standards

7.  Long Non-coding RNAs Can Encode Proteins After All

8.  Proteins and cellular adaptation to stress

9.  Loss of normal growth regulation


Posttranslational modification is a step in protein biosynthesis. Proteins are created by ribosomes translating mRNA into polypeptide chains. These polypeptide chains undergo
PTM before becoming the mature protein product.

Regulation of somatic stem cell Function by DNA Methylation and Genomic Imprinting

Mo Li1, Na Young Kim1, Shigeo Masuda1 and Juan Carlos izpisua Belmonte1,2 1Salk institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA. 2Center of Regenerative Medicine in Barcelona, Dr Aiguader, 88, 08003 Barcelona, Spain. Corresponding author email:

Cell & Tissue Transplantation & Therapy 2013:5 19–23
This article is available from


Epigenetic regulation is essential for self-renewal and differentiation of somatic stem cells, including

  • hematopoietic stem cells (HSCs) and
  • neural stem cells (NSCs).

The role of DNA methylation, a key epigenetic pathway,

  • in regulating somatic stem cell function
    • under physiological conditions and during aging

has been intensively investigated.

Accumulating evidence highlights the dynamic nature of

  • the DNAmethylome
    • during lineage commitment of somatic stem cells and
  • the pivotal role of DNAmethyltransferases in
    • stem cell self-renewal and differentiation.

Recent studies on genomic imprinting have shed light on

  • the imprinted gene network (IGN) in somatic stem cells,
  1. where a subset of imprinted genes remain expressed and
  2. are important for maintaining self-renewal of these cells.

Together with emerging technologies, elucidation of the epigenetic mechanisms regulating somatic stem cells with normal or pathological functions may contribute to the development of regenerative medicine.

Keywords: somatic stem cells, epigenetics, DNA methylation, genomic imprinting, hematopoietic stem cells, neural stem cells


In adult animals, somatic stem cells (also known as adult stem cells) are responsible for maintaining tissue homeostasis and participate in tissue regeneration under injury conditions. Self-renewal and differentiation are two important aspects of somatic stem cell function. Epigenetic mechanisms underlying these processes have been intensively investigated. With the increasing ability

  • to identify and manipulate somatic stem cell populations from diverse tissues,
  • it is possible to dissect the epigenetic pathways that are
  1. either unique for a specific tissue or
  2. universally important in regulating stemness and differentiation.

Epigenetic control of somatic stem cell function exists at various levels, including

  • DNA methylation,
  • histone modification, and
  • higher-order chromatin structure dynamics.

Here, we focus on recent progress in our understanding of how

  • DNA methylation regulates somatic stem cell function.

DNA Methylation and stem cell Function

The role of DNA methylation in somatic stem cell compartments has gained increasing attention. Recent  evidence has shown that

  • DNA methylation is dynamically regulated during somatic stem cell differentiation and aging.1

A study of methylomes of human hematopoietic stem cells (HSCs) and two mature hematopoietic lineages,

  • including B cells and neutrophils, showed that
    • hypomethylated regions of lineage-specific genes often become methylated in opposing lineages, and that
    • progenitors display an intermediate methylation pattern

that is poised for lineage-specific resolution.2

Another study compared genome-wide promoter DNA methylation in human cord blood hematopoietic progenitor cells (HPCs) with

  • that in mobilized peripheral blood HPCs from aged individuals.

It was found that aged HPCs lose DNA methylation in a subset of genes that are hypomethylated in differentiated myeloid cells and

  • gain de novo DNA methylation at polycomb repressive complex 2 (PRC2) target sites.3

It was hypothesized that such epigenetic changes contribute to age-related loss of HSC function, such as a bias toward myeloid lineages. Recently, Beerman et al. studied the global DNA methylation landscape of HSCs in the context of

  • age-associated decline of HSC function.4

Over- all, the DNA methylation landscape remains stable during HSC ontogeny. However, HSCs isolated from old mice display higher global DNA methylation. Interestingly, they observed

  • localized DNA methylation changes in genomic regions associated with hematopoietic lineage differentiation.

These methylation changes preferentially map to genes

  • that are expressed in downstream progenitor and effector cells.

For example, genes that are important for the lymphoid and erythroid lineages

  • become methylated in “old” HSCs,

which is consistent with

  • the decline of lymphopoiesis and erythropoiesis during aging.

Additionally, inducing HSC proliferation by 5-fluorouracil treatment or

  • by limiting the number of transplantedHSCs
    • recapitulates the functional decline and DNA methylation changes during physiological aging.

A closer examination of the overlapping genes with significant DNA methylation changes during aging or enforced proliferation showed

  • an enrichment of DNA hypermethylation at PRC2 target loci,

echoing the observation by Bocker et al. in human HSCs.

Interestingly, a recent report showed that epigenetic alterations such as DNA hypermethylation that are accrued during aging,

  • can be fully reset by somatic reprogramming,

raising an interesting possibility that these aging-related epigenetic defects may be reserved by small molecules.5

Methylation of cytosines at CpG dinucleotides is catalyzed by three key enzymes.

DNA (cytosine-5)- methyltransferase 1 (DNMT1) is responsible for maintaining DNA methylation patterns during DNA replication

  • by methylating the newly synthesized hemi-methylated DNA.

The other two DNA methyltransferases, DNMT3a and DNMT3b,

  • are not DNA replication-dependent and can methylate fully unmethylated DNA de novo.

They are responsible for establishing new DNA methylation patterns during development.

DNMT3a, a gene required for neurogenesis,

  • is expressed in postnatal neural stem cells (NSCs).

In NSCs, DNMT3a methylates non-proximal promoter regions, such as gene bodies and intergenic regions. Surprisingly, rather than silencing gene expression,

DNMT3a-mediated DNA methylation in gene bodies antagonizes Polycomb-dependent repression and

  • facilitates the expression of neurogenic genes.6

The role of DNMT3a in HSCs has also been investigated. Both Dnmt3a and Dnmt3b are expressed in HSCs. An earlier study did not identify any defects in HSC function when Dnmt3a or Dnmt3b was removed.  However,

  • HSCs lackingboth of these de novomethyltransferases
    • fail to self-renew, yet retain the capacity to differentiate.7

A more recent study re-examined

  • the consequences of Dnmt3a loss in HSCs and
  • uncovered a progressive defect in differentiation that is only manifested during serial transplantation.8

At the molecular level, while Dnmt3a loss results in the expected hypomethylation at some loci,

  • it counterintuitively causes hypermethylation in even more regions.8

This seemingly paradoxical result echoes the  unconventional role of Dnmt3a in transcriptional  activation in NSCs (as discussed above). Both cases suggest a more complex regulatory function of DNMT3a that is

  • beyond simply methylating DNA.

In contrast, the loss of Dnmt1 produces more dramatic and immediate phenotypes in HSCs, manifested

  • in premature HSC exhaustion and
  • block of lymphoid differentiation,

highlighting the distinct requirements for different DNA methyltransferases in HSCs.9,10

Genomic Imprinting and stemness

DNA methylation also underlies genomic imprinting, which is an

  • evolutionarily conserved epigenetic mechanism of ensuring appropriate gene dosage during development.

One allele of the imprinted genes is

  • epigenetically marked by DNA methylation to be silenced according to the parental origin.

The pattern of imprinting

  • is established in germ cells and maintained in somatic cells.

Imprinted genes are thought to play critical roles in organismal growth and are relatively downregulated after birth.11 Recently, a series of reports demonstrated that

  • a subset of imprinted genes belonging to the purported imprinted gene network (IGN)12
  • remain expressed in somatic stem cells and
  • are important for maintaining self-renewal of these cells.

Through gene expression profiling, one group identified that several members of the IGN are expressed in

  1. murine muscle,
  2. epidermal, and
  3. long-term hematopoietic stem cells
  4. as well as in human epidermal and hematopoietic stem cells.13

In particular, the paternally expressed gene 3 (Peg3) gene was shown by another group

  • to mark cycling and quiescent stem cells in a wide variety of mouse tissues.14

The role of imprinted genes in regulating somatic stem cell function has been examined in two types of tissues.

In bronchioalveolar stem cells (BASCs), a lung epithelial stem cell population,

  • expression of IGN members is required for their self-renewal.

Bmi1, a polycomb repressive  complex 1 (PRC1) subunit,

  • is essential for controlling the expression of imprinted genes in BASCs without affecting their imprinting status.15

In Bmi1 mutant BASCs,  many members of the IGN become derepressed,

  • including p57, H19, Dlk1, Peg3, Ndn, Mest, Gtl2, Grb10, Plagl1, and Igf2.

Knockdown of p57, which is the most differentially expressed imprinted gene between normal and mutant BASCs,

  • partially rescues the self-renewal defect of lung stem cells.

Interestingly, insufficient levels of p57 also inhibit self-renewal of lung stem cells. Because p57 expression

  • remains monoallelic in Bmi1 knockdown cells,
  • Bmi1 is thought to maintain an appropriate level of expression from the expressed allele of p57.15

Another IGN member- delta-like homologue 1 (Dlk1) has been shown to be important for postnatal neurogenesis. Interestingly, in this context,

  • Dlk1 loses its imprinting in postnatal neural stem cells and niche astrocytes.16

These studies suggest that modulating IGN may represent another

  • epigenetic mechanism for balancing self-renewal and differentiation in somatic stem cells.

Thus, somatic stem cells either co-opt or remodel these developmental pathways involving the IGN

  • to fulfill the needs of tissue homeostasis during the adult stage.

In summary, several factors participate in regulating the epigenome of somatic stem cells.

Perturbations in the epigenome of somatic stem cells,

  • either during organismal aging or under pathological conditions,

will tip the balance between self-renewal and differentiation of somatic stem cells (Fig. 1). A detailed understanding of the mechanisms underlying these changes will likely result in novel therapeutic approaches targeting somatic stem cells.

Figure 1. The epigenome of somatic stem cells is regulated by diverse factors.

Future perspectives The epigenetic mechanisms governing self-renewal and differentiation of somatic stem cells are likely to be complex because of the diverse needs of different tissues. It would be interesting to determine whether a common mechanism, such as the IGN, exists across different somatic stem cells. Additionally, study- ing epigenetic pathways that are specific to one type of somatic stem cell requires the isolation of these cells and their differentiated progeny, which is more practical in model organisms than in humans. Along these lines, developing robust in vitro culture methods for human somatic stem cells and protocols for differentiating these cells into specific lineages are critical for uncovering epigenetic pathways that are unique to human somatic stem cells. In recent years, the field has seen a great improvement in methods of directed differentiation of human embryonic stem cells and induced pluripotent stem cells (iPSCs). For example, it is relatively straightforward to produce high-purity cell populations that resemble neural stem cells or mesenchymal stem cells from iPSCs.17

These methodologies not only are useful for studying the normal function of somatic stem cells, but also provide an exciting opportunity for understanding the role of somatic stem cells in disease pathology and a platform to screen for drugs. A recent study under- scored the usefulness of this approach. Liu et al. studied neural stem cells derived from Parkinson’s disease human iPSCs and uncovered previously unknown defects in nuclear morphology and epigenetic regulation in these derived NSCs.18 The cellular defects only menifest in “aged” neural stem cells, which is consistent with the fact that Parkinson’s disease pri- marily manifests in old age. More  importantly, this study identified neural stem cell as a potential target of therapeutic intervention for Parkinson’s disease.

Targeted modification of the human genome is  another technological advancement that is on the horizon to greatly facilitate the dissection of epige- netic pathways in somatic stem cells. Although gene targeting in somatic stem cells has been historically challenging, there have been encouraging successful reports following development of new genome-e diting technologies, such as Helper-dependent adenovi- ral vectors, TALENs, and CAS9/CRISPR. With the development of these new technologies, it seems that the stage has been set for a new wave of discoveries in epigenetic mechanisms of somatic stem cells.


1. Li M, Liu GH, Izpisua Belmonte JC. Navigating the epigenetic landscape of pluripotent stem cells. Nat Rev Mol Cell Biol. 2012;13(8):524–535.

2. Hodges E, Molaro A, Dos Santos CO, et al. Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol Cell. 2011;44(1):17–28.

3. Bocker MT, Hellwig I, Breiling A, Eckstein V, Ho AD, Lyko F. Genome- wide promoter DNA methylation dynamics of human hematopoietic progen- itor cells during differentiation and aging. Blood. 2011;117(19):e182–e189.

4. Beerman I, Bock C, Garrison BS, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12(4):413–425.

5. Wahlestedt M, Norddahl GL, Sten G, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood. 2013;121(21):4257–4264.

6. Wu H, Coskun V, Tao J, et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 2010; 329(5990):444–448.

7. Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H. De novo DNA meth- yltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med. 2007;204(4):715–722.

8. Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011;44(1):23–31.

9. Broske AM, Vockentanz L, Kharazi S, et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet. 2009;41(11):1207–1215.

10. Trowbridge JJ, Snow JW, Kim J, Orkin SH. DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell. 2009;5(4):442–449.

11. Wood AJ, Oakey RJ. Genomic imprinting in mammals: emerging themes and established theories. PLoS Genet. 2006;2(11):e147.

12. Lui JC, Finkielstain GP, Barnes KM, Baron J. An imprinted gene network that controls mammalian somatic growth is down-regulated during postna- tal growth deceleration in multiple organs. Am J Physiol Regul Integr Comp Physiol. 2008;295(1):R189–R196.

13. Berg JS, Lin KK, Sonnet C, et al. Imprinted genes that regulate early mam- malian growth are coexpressed in somatic stem cells. PLoS One. 2011; 6(10):e26410.

14. Besson V, Smeriglio P, Wegener A, et al. PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell popu- lations. Proc Natl Acad Sci U S A. 2011;108(28):11470–11475.

15. Zacharek SJ, Fillmore CM, Lau AN, et al. Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci. Cell Stem Cell. 2011;9(3):272–281.

16. Ferron SR, Charalambous M, Radford E, et al. Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature. 2011;475(7356):381–385.

17. Li W, Sun W, Zhang Y, et al. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proc Natl Acad Sci U S A. 2011;108(20):8299–8304.

18. Liu GH, Qu J, Suzuki K, et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 2012;491(7425):603–607.


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