Nutrition and Epigenetics

1. Youngson Neil A. and Morris Margaret J. 2013What obesity research tells us about epigenetic mechanismsPhil. Trans. R. Soc. B3682011033720110337
http://doi.org/10.1098/rstb.2011.0337.

2.Dai, Z., Ramesh, V. & Locasale, J.W. The evolving metabolic landscape of chromatin biology and epigenetics. Nat Rev Genet 21, 737–753 (2020).
https://doi.org/10.1038/s41576-020-0270-8
3.Huang, Z., Cai, L., & Tu, B. P. (2015). Dietary control of chromatin. Current opinion in cell biology, 34, 69–74. https://doi.org/10.1016/j.ceb.2015.05.004

Ayşegül OSMANOĞLU, Zeyno Lee LEVICKI

1.1 Metabolites are connected to Epigenetic pathways
Metabolism is the result of networks of biochemical reactions that take in
nutrients in order to process them to serve cellular demands, including
energy generation and biosynthesis .
12

Intermediates of these reactions are used as substrates and cofactors for

a variety of epigenome-modifying enzymes , allowing metabolism to
13

directly communicate environmental changes to the chromatin state

Image1: Influences of environmental factors
on histone acetylation and methylation.
1.2 Why Certain Familiar Nutrients ?
Intermediates that can be utilized in histone modification, the fundamental
process that drives epigenetic utilizes certain donor molecules, or is
modified by intermediary enzymes.
Familiar nutrients like folic acid, B vitamins, and SAM-e (S-
Adenosyl methionine, a popular over-the-counter supplement) are key
components.
2.1.Chromatin Remodelers use Cofactors derived from
the Metabolic Pathway/Methylation
HMTs are regulated through SAMs which are molecules used for methylations,
HDMs are regulated by alpha-ketoglutarate. Both of which are related to metabolism.
Specifically, SAH is a potent inhibitor of DNA Methyltransferases (DNMTs) and
Histone Methyltransferase (HMTs) whereby the cellular concentration of SAH
determines the activity of methyltransferases

LSD1, demethylase(H3K4me2/1, H3K9) that utilizes FAD as cofactor and

regulates energy expenditure genes in adipocytes.
Image 1:Methionine Cycle
2.2. The metabolic enzymes can also translocate to the
nucleus, where they can locally produce substrates for
chromatin modification.

Image 2:Nutrients and Epigenetic

2.3.Chromatin Remodelers use Cofactors derived from
the Metabolic Pathway/Acetylation

Acetylation of histones, which

involves the transfer of an acetyl
group derived from the high-
energy metabolite acetyl-CoA to
the ε-amino group of a histone
lysine, catalysed by
acetyltransferases.

Image 3: 1 TCA cycle

Cycles of histone acetylation and deacetylation occur continuously and
rapidly throughout the genome, consuming ac-CoA and generating
negatively charged acetate anions in the process. Since ac-CoA and
acetate anions participate in many metabolic processes, like:

DHATs also have a role in cellular pH

stabilization, as cellular pH decreases
histones are deacetylated and the
acetate ions are co-exported with
protons by monocarboxylate
transporters.
It was shown in a study that,
minimum levels of
Glutamine(G) and Pyruvate(P)
are required to maintain
normal levels of Histone
Acetylation
Cycles of histone acetylation and deacetylation occur continuously and rapidly throughout
the genome, consuming ac-CoA and generating negatively charged acetate anions in the
process. Since ac-CoA and acetate anions participate in many metabolic processes

What might be the mechanism by which HATs respond to altered acetyl-CoA

concentrations?

One possible mechanism is that the binding affinity of the enzymes for acetyl-CoA is in the range of in
vivo fluctuations of acetyl-CoA concentrations.

Further speculation is that nuclear localization of the acetyl-CoA-producing enzymes

may be induced during growth phases and may directly provide acetyl-CoA to the histone-
acetylating enzymes.
2.3.Chromatin Remodelers use Cofactors derived from
the Metabolic Pathway/Deacetylation
A type of DHAT known as type 3, sirtuins, is known to use NAD+ as a cofactor which indicated
a correlation between cellular NAD+ levels and chromatin regulation.

It appears that the decrease in NAD levels during aging affects SIRT1 activity and
+

thereby the control of nuclear-encoded mitochondrial genes.

During aging, each of the three major NAD -consuming pathways may be activated and
+

competes for NAD as a substrate.In fact, requirement for DNA repair is recognized to
+

contribute to 80% of NAD decline, and aging is a known cause of DNA oxidative damage
+
Image4: Physiology and Epigenetic
3.1.Epigenetic Regulation in Different Physiological Context/Immunology

Antigen receptor engagement in T cells, for example, has been shown to increase
metabolic flux through the methionine cycle, which upregulates DNA and histone
methylation.

Methionine uptake has also been shown to maintain SAM synthesis and H3K4me3
levels in CD4+ T helper (TH) cells in culture, which regulates T cell-mediated
immune responses in vivo in a mouse model of multiple sclerosis.
3.1.Epigenetic Regulation in Different Physiological Context/Immunology

Iron(II) deficiency was found to

induce defects in the humoral immune response

due to impaired activities of iron-

dependent JHDMs and H3K9
hypermethylation at the promoter
region of cyclin E, an important
element for B cell proliferation . 61
3.2.Epigenetic Regulation in Different Physiological Context/Differentiation
Metabolic pathway activity
and nutrient availability have
been associated with cell-
fate-related outcomes, such
as induced pluripotency,
maintenance of stemness and
differentiation towards
specific lineages
Disruption to one-carbon
metabolism has been shown
to regulate embryonic stem cell
(ESC) differentiation through
changes in SAM levels, both in
culture and in mice, along with
changes to histone methylation
and DNA methylation
Image 5: 1(One) Carbon Metabolism
3.2.Epigenetic Regulation in Different Physiological Context/Differentiation

Modulating acetyl-CoA
levels can affect the
differentiation of ESCs
and muscle stem cells,
with concurrently
occurring changes in
histone acetylation and
chromatin accessibility.

Image 6: Acetylation and muscle cell

differentiation
3.3.Epigenetic Regulation in Different Physiological Context/Cancer
Metabolic genes involved in producing
chromatin-modifying metabolites are
also frequently mutated in cancers,
suggesting that the metabolically
regulated epigenomic landscape has
critical roles in cancer biology
The most well-known example is the
mutation of IDH1 or IDH2.
Isocitrate dehydrogenase 1 and 2
(IDH1 and IDH2) are key metabolic
enzymes that convert isocitrate to α-
ketoglutarate. IDH1/2 mutations define
distinct subsets of cancers, including
low-grade gliomas and secondary
glioblastomas, chondrosarcomas,
intrahepatic cholangiocarcinomas, and
hematologic malignancies.
 Mutant IDH1 or IDH2 can lead to
DNA and histone hypermethylation
through the accumulation of 2-HG,
resulting in the downregulation of
genes associated with tumour
suppression

Image 7: IDH missense mutation leading to D-2HG

accumulation
Also frequently mutated in cancer are
genes encoding the metabolic enzymes
FH and SDH, whose deficiency leads
to the accumulation of fumarate and
succinate, respectively; both of these
metabolites inhibit TETs and JHDMs,
resulting in genome-wide DNA and
histone hypermethylation.

Image 8: FH and SDH mutation leading to Fumarate and Succinate

accumulation
Image 9: Influences of environmental factors
on histone acetylation and methylation.
4.1.Epigenetic Regulation in relation to DIET/Calorie Restriction(CR)
Calorie restriction (CR), which reduces total daily calorie intake by around 15–40%

Prolonged CR has been previously shown to extend lifespan and generate positive health outcomes
in model organisms such as yeast, fruit flies, mice and monkeys, through a variety of metabolic
and physiological effects

Generation of the ketone body(breakdown of fatty acids and ketogenic amino acids, in a process
named ketogenesis, which is a metabolic adaptation to fasting) β-OHB is a consequence of CR that
mediates these phenotypes

β-OHB has multifaceted roles in regulating chromatin modifications: it can inhibit class I HDACs,
causing a global upregulation of histone acetylation, and can serve as a substrate for histone β-
hydroxybutyrylation, a mark enriched at active promoters and associated with the upregulation of
starvation-responsive metabolic pathways
Image 10: Formation of β-OHB and
starvation related gene acetylation
4.2.Epigenetic Regulation in relation to DIET/Alcohol Consumption

In vertebrate models, CREB signaling in the amygdaloid circuitry plays an important role in
regulating ethanol-related behaviors and in mediating the anxiolytic effects of ethanol


In the central and medial nucleus of the amygdala, after acute administration of ethanol we
observed increased CREB phosphorylation, CBP levels, histone H3 and H4 acetylation, and
neuropeptide Y (NPY) expression in addition to producing anxiolytic effects.

This was shown to affect the activation of transcriptional programmes related to learning
and memory, influencing alcohol-related reward behaviour.
5.1. Abnormal Epigenetic Fluctuations caused by early developmental diet
and its multi-trait physiological modifications in adult life

The greatest area of research on the involvement of epigenetic mechanisms in obesity is on the
developmental origins of adult health and disease (DOHaD), otherwise known as
gestational/fetal/developmental programming.

The types of early-life experience that have been shown to cause this include changes to nutrition
(excess and starvation), chemical exposures and stresses

Obesity is part of a range of programmed disorders that are collectively known as ‘metabolic
syndrome’, the others being hyperglycaemia, insulin resistance, hyperlipidemia, hyperinsulinemia and
hypertension. The cause of the syndrome is thought to be due to a mismatch in the environment
experienced by the organism during development compared with later life
5.2. OBESITY is a complex pathological disorder that’s also associated with early
developmental epigenetic methylation affecting: Sensory, neurotransmitter,
hormone expressions

Obesity is one among several programmed disorders collectively known as 'metabolic syndrome,' which
includes hyperglycemia, insulin resistance, hyperlipidemia, hyperinsulinemia, and hypertension. The origin
of this syndrome is believed to stem from a mismatch between the organism's developmental environment
and the conditions encountered later in life.

In instances where an individual is programmed due to early-life experiences such as abnormal shortage of
food (e.g., famine) or exposure to chemicals that mimic famine programming, the physiological signals
persist even in times of abundant food supply. This enduring response may contribute to the development
and persistence of metabolic syndrome traits, including obesity, despite a shift to a more nutrient-rich
environment. 
and the mismatch could lead to obesity