Metabolism influences epigenetics through the production of intermediary metabolites that serve as substrates or cofactors for epigenetic enzymes. Key metabolites such as acetyl-CoA, S-adenosyl methionine (SAM), alpha-ketoglutarate (α-KG), nicotinamide adenine dinucleotide (NAD+), and flavin adenine dinucleotide (FAD+) fuel the activities of histone modifying enzymes and DNA methyltransferases. Changes in metabolite levels can therefore alter the epigenetic landscape by impacting chromatin structure and gene expression. Nutrients also influence this interplay, as they directly impact metabolism and the availability of metabolites that regulate the ep

1. INTERPLAY BETWEEN
METABOLISM AND
EPIGENETICS
PRESENTED BY : ABHISHEK M
Department of Human Genetics and Molecular Medicine
Central University of Punjab, Bathinda
REGD NO : 17MSLSHG09
DATE : 7/2/2018

2. What is epigenetics?
• Term coined by C.H. Waddington.
• Epigenesis - Extra growth
• Epi(in Greek) - Above or over or
around.
• Heritable changes in gene function that
do not involve changes in the DNA
sequence.
• It could be endogenous or exogenous.
Source: http://www.eoht.info/page/Conrad+Waddington

3. Source: http://www.salariuspharma.com/epigenetics.html

4. Epigenetic categories
• Self-sustaining metabolic loops.
• Structural templating in which structures are replicated using a
template or scaffold structure on the parent.
• Chromatin marks, in which methyl or acetyl groups bind to
DNA nucleotides or histones thereby altering gene expression.
• RNA silencing, in which small RNA strands interfere (RNAi) with the
transcription of DNA or translation of mRNA.

5. FIG: Various Epigenetic interactions
Source: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003007

6. How does metabolism influence
Epigenetics?
Activity of most enzymes involved in dynamic chromatin modification is
dependent on intermediary metabolites. These include:-
• Acetyl CoA
• SAM
• ATP
• NAD+
• FAD
• α-KG, etc.

7. Acetyl CoA and Histone acetylation
• Histone Acetyl Transferases(HATs) uses Acetyl CoA as substrate.
• Acetylation of lysine residues in histones.
• Positively charged residues are neutralized.
• Opens up chromatin structure.

8. Source: https://library.med.utah.edu/NetBiochem/FattyAcids/2_4.html

9. FIG: Reaction between Acetyl CoA and lysine
Source: http://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(10)00196-9

10. FIG: Histone Acetylation
Source: http://www.cell.com/molecular-cell/pdf/S1097-2765(16)30192-7.pdf

11. Sirtuins, NAD+ and Histone Deacetylation
• NAD+ functions as an obligated cofactor for the
class III histone deacetylase (HDAC) enzymes
known as sirtuins.
• SIRT1, 2, 6, and 7 are localized in the nucleus and
target the deacetylation of specific histone residues.
• The decrease in levels of NAD+ has a negative
effect on SIRT activity, especially SIRT1.
• SIRT6 deficiency causes genomic instability along
with a severe and fatal hypoglycemia. Source: https://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide

12. FIG: Deacetylation reaction by Sirtuins
Source: https://plasticsurgerykey.com/sirtuins-and-skin/

13. FIG: Histone Deacetylation
Source: http://www.cell.com/molecular-cell/pdf/S1097-2765(16)30192-7.pdf

14. SAM and DNA/Histone methylation
• Methylation of both histone H3 and H4 occurs at lysine
and arginine residues.
• Histone methylation is an epigenetic mark associated with
either repression or activation of transcription.
• Cytosine can be methylated by the DNA
methyltransferase enzymes DNMT1, DNMT3a, and
DNMT3b.
• SAM is the universal donor of methyl groups to both
kinds of methyl transferases.

15. FIG: Methyl transfer reaction
Source: https://en.wikipedia.org/wiki/Methyltransferase
FIG: S-Adenosyl Methionine
Source: https://en.wikipedia.org/wiki/S-
Adenosyl_methionine

16. FIG: DNA Methylation
Source: https://www.researchgate.net/figure/6079123_fig2_Figure-1-CpG-methylation-A-Mechanism-
of-DNA-methylation-B-CpG-methylation-is

17. FAD+ and α-KG Involved in Histone/DNA Demethylation
• There are two classes of evolutionary conserved family of histone
demethylases, the LSD and the Jumonji C (JmjC) domain-containing
proteins.
• LSD1 uses FAD+ as a cofactor.
• JmjC domain-containing enzymes function in an iron (Fe2+) and α -
KG-dependent demethylation reaction

18. FIG: FAD (Flavin adenine dinucleotide)
Source: https://en.wikipedia.org/wiki/Flavin_adenine_dinucleotide
FIG: α-Ketoglutaric acid
Source: https://en.wikipedia.org/wiki/Alpha-Ketoglutari

19. FIG: The mechanism of Demethylation of Lysine present in the histones
Source: http://www.abcam.com/index.html?pageconfig=resource&rid=11182

20. FIG: Methylation and Demethylation of DNA
Source: http://www.cell.com/molecular-cell/pdf/S1097-2765(16)30192-7.pdf

21. Other metabolites involved in chromatin modifications
• Phosphorylation (Depending on ATP availability)
• O-GlcNAcylation (O-linked N-acetylglucosamine)
• Sumoylation
• Ubiquitination
• Acylations like butyrylation, malonylation,
crotolylation etc.

22. FIG: O-GlcNAcylation of Histones
Source: http://www.cell.com/molecular-cell/pdf/S1097-2765(16)30192-7.pdf

23. FIG: Interactions of various metabolites and epigenetic enzymes

24. Nutrients and its effects on metabolism and epigenetics
• Nutrients are essential for the growth and development of organisms.
• They directly influence the metabolism of the body.
• Folic acid plays important role in DNA methylation.
• Dietary fiber intake helps in Histone Acetylation.

25. FIG: Nutrients and Epigenetics.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038610/

30. References:
Research Papers:
1. Epigenetics and Cellular Metabolism, Wenyi Xu, Fengzhong
Wang, Zhongsheng Yu, and Fengjiao Xin. Published online 2016 Sep
25. doi: 10.4137/GEG.S32160.
2. Interplay between Metabolism and Epigenetics: A Nuclear
Adaptation to Environmental Changes Jean-Pierre Etchegaray and
Raul Mostoslavsky. http://dx.doi.org/10.1016/j.molcel.2016.05.029
3. When Metabolism and Epigenetics Converge, Paolo Sassone-Corsi.
Vol. 339, Issue 6116, pp. 148-150, DOI: 10.1126/science.1233423
4. Metabolic Regulation of Epigenetics,Chao Lu, Craig B.Thompson,
https://doi.org/10.1016/j.cmet.2012.06.001
5. Epigenetics and Metabolism, Samuel T. Keating, Assam El-Osta,
https://doi.org/10.1161/CIRCRESAHA.116.303936

31. Websites:
1. www.wikipedia.com
2. www.nature,com
3. www.trustedcarechiro.com
4. www.salariuspharma.com