Friday, May 27, 2016

Do adult stem cells form by lineage commitment or from normal differentiated cells?

As adult stem cells are different from differentiated cells only in transcription profile, maybe they just form form differentiated cells if there is a need for them?
There is some evidence in this thesis that differentiated cells can de differentiate into the originating stem cell state, however transformation into different cell type is unusual. This is kind of expected if DNA methylation indeed determines cell type, but stemness is only determined by gene expression which is much more plastic.
 

Epigenetic modifications of aging have weak direct link on the expression profile

 Steve Horvath reported he had found no universal transcription profile signature of aging.
However there is clearly and aging phenotype of cells. I mean functional decline of the cell. (think of immunosenescene for starters)
Maybe this is caused by transcriptional noise resulting from hypomethylation of repetitive elements (and others)?

Study
Longitudinal epigenetic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes involved in protein translation in human aging

Fibroblast samples from same person after 10+ years analysed for expression, DNA methylation and certain histone modifications. Shockingly very weak correlation between upregulated sequences and methylation or histone modification.
Expression profile changes match phenotype changes of aging (metalloproteins upregulated , collagen downregulated).

Previous entry concluded stem cells differ not in DNA methylation but in transcription profiles
Maybe its the plasticity and potency of stem cells that is affected by the epigenetic clock by methylating PRC targets. What we see in expression profiles of fibroblasts is the profile of fully differentiated cells, probably different from stem cell profiles.

Wednesday, May 25, 2016

Histone modification upstream of DNA methylation?

We know that DNA methylation patterns are the best predictors of chronological age.
http://www.nature.com/news/biomarkers-and-ageing-the-clock-watcher-1.15014
In this study:
Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging
age dependent lactose intolerance is  investigated.
Lactase enzyme DNA is downregulated in mouse by day 60 and in humans by the second decade of life.
This is achived by increased methylation of the lactase gene DNA.
However there are populations that do not show age related loss of lactose tolerance. DNA of lactase does not get methylated by age in these individuals. The article points to H3K4me1 and H3K27ac histone modifications in the differentially methylated regions. In these regions age related methylation is overcome in lactose tolerant individuals. The  epigenetic clock is selectively stopped here.

Another article also underpins the role of histone modifications in DNA methylation patterns
Molecular coupling of DNA methylation and histone methylation

" DNA methylation is associated with the absence of H3K4 methylation (H3K4me0) and the presence of H3K9 methylation, but has little correlation with methylation of H3K2"

Tuesday, May 24, 2016

DNA methylation specifies cell type but not stemness

Paper:

DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus

Takeaway

There is very little difference in DNA methylation between adult intestinal stem cells and the fully differentiatiated villus cells deriving from them. Only a couple of ten promoters show differential DNA methylation.
DNA methylation defines cell type, not status of differemtiation.
There are hypomethylated regions in differentiated cells, their expression increased - transcription factor binding? Histone modifications also observed with DMRs (differentially methylated regions)
Slight general hypomethylation was observed  in differentiated cells.

Thoughts:

The driver behind aging related  hypermethylation  -  maybe reduced TF binding over time?
Aging related hypomethylation - lack of methylation maintenance  ?

My earlier notes

  1. Histone methylation vs DNA methylation
DNMT3a3b vs PRC1/2.
DNA methylation degrades bivalent chromatin
Epigenetic drift

2. DNA methylation better predictor of chronological age than telomerase
  

3. DNMT3a

4. Bivalent chromatin
Bivalent promoters control hundreds or thousand genes, differentiation and tissue specific

5. Cancer DNA methylome

PCR2 during embryonal stem cell differentiation

DNA methylation and histone meth in aging mouse HSCs, very thorough
p16INK4a not upregulated in old stem cell

HSC renewal caused by DNMt3a mutation (effectively knock down)  induces leukemia

9. melatonin and aging


10. Tissue maintenance

11. Epigenetic dysregulation, stem cells

12. Aging and epigenetic drift
13.  review on dna methylation

14. review on histone methylation

Age-Associated Hyper-Methylated Regions in the Human Brain Overlap with Bivalent Chromatin Domains
16. hsc exhaustion by methylation of prc2 targets

17. Tumor microenvironment immune suppression is PTEN dependent

18. epigenetic deregulation is a common feature of aging in mammals

19. DNMT1 decreases with aging, citations


20. Aging and DNA methylation. Very good

21. chromatin in aging and cancer (methylation, histones, ncRNA)

Transcriptome landscape in human genome

23. Partial hepatectomy, lncRNA regulates regeneration

24. Long non coding RNA really like to guide PRC2
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514479/

25. surprise, aging can impair regeneration of liver

Epigenetic regulation of ageing: linking environmental inputs to genomic stabilit

Very good
free on researchgate
it’s the chromatin, stupid!

26. Mouse strains survival curves

27. Naked mole rate sequencing

Cellular senescence and the senescent
secretory phenotype: therapeutic opportunities

Adult ‐ onset, short ‐ term dietary restriction reduces cell senescence in mice

Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in
cellular senescence

Regulation of p16/INK4 (PRC2 and histone modification involved)


PRC2 meets senescence

33. p16 hypermethylation increases age related cancer incidence in mice
seems like the epigenetic dysregulation of the genome, which upregulates many sequences, also upregulatesp16 thus inherently protecting against cancer -> lowering the threshold toward degenerating into senescencent phenotype

is there anything that drives epigenetic dysregulation or is it just enthropy?

34. or histone deacethylase??

35. Good thorough paper on time restricted feeding in mice. Unfortunately no lifespan or health span investigation, only biomarkers. Very good effects on serum insulin and cholersterol.

36. mTOR regulates circadian rythm?

37. Transposable elements drive ageing


38. mtDNA mutations in oocytes are much less frequent than in somatic cells

While somatic cells depend mostly on mitochondrial oxidative phosphorylation (OxPhos), pluripotent stem cells possess immature mitochondria and preferentially use glycolysis as their major source of energy

DNA demethylation

41. Overexpression DNMR3b1 but not DNMT3a1 of cancer prone trangenic mice increases tumor incidence. Same pathway (igf2 overexpression by suppressing H19) as in DNMT1 overexpression study,
Maybe DNMT3a can be overexpressed without adverse effects?
The article has a nice inrroduction where they state the cancer cells are generally hypomethylated byt hypermethylated at PRC2 binding sites. This is exactly the same as the findings about aging stem cell.

42. Adult stem cell epigenetics, very good
https://www.researchgate.net/profile/Lorenzo_Rinaldi2/publication/264199997_Epigenetic_regulation_of_adult_stem_cell_function/links/5629e16308ae22b1703159ad.pdf