Epigenetics

Modifications that change information in DNA without changing the sequence of nucleic acids
1. They create these changes through regulatory components of gene expression
  1. DNA methylation
    1. Hypomethylation
      1. Increased gene expression
    2. Hypermethylation
      1. Decreased gene expression
        Changes in DNAs hydrophobic property
    3. Two types of enzymes involved
      1. DNA methyltransferases (DNMT)
        1
        Classical maintenance methyltransferase
        It is in charge of maintenance of methylation pattern during DNA replication
        Homozygous and heterozygous knockdown is lethal
        2
        Catalyze mainly RNA
        3A AND 3B
        Participate in the establishment of de novo methylation patterns during early embryonic development
        Its expression is regulated by hypoxic stress
      2. Ten-eleven translocation methylcytosine dioxygenases (TET)
        It demethylates DNA
        Essential role in embryonic maintenance and ICM specification
        Codified by three genes
        Knockdown of all three produces complete arrest of embryonic development
        Its effects are significantly reduced under hypoxic conditions
    4. Mainly in the cytosine nucleotides in the promoter region
      1. CpG dinucleotides
  2. Histone modifications
    1. Histones come in five basic forms
      1. They form nucleosomes with the DNA
    2. Enzymes associated
      1. Histone acetyltransferases (HAT)
      2. Histone methyltransferases (HMT)
      3. Histone deacetylases (HDAC)
        Maternal protein deprivation down regulates mTOR pathwoy, important for its activity
      4. Histone demethylases (HDM)
      5. They regulate promoter activity, chromatin structure, dosage compensation and epigenetic memory
    3. They can be induced by maternal or paternal stress
  3. Regulation by noncoding DNA
    1. miRNA
      1. It silences post-transcriptional process, gene translation, targeting the 3´UTR
        Then, it supresses gene expression in a sequence-specific manner
      2. It can cross the placental barrier and regulate maternal, placental or fetal tissues
    2. Long noncoding RNA (IncRNA)
      1. It regulates cellular differentiation and organism developmental
        Neuronal, muscle, heart differentiation
      2. It affects adipogenesis and beta cell formation
      3. It can fold and serve as sponge for mi RNA or as scaffold for proteins in regulatory complexes
Changes caused by many factors
1. Environmental
  1. Exposure of the father to cold
    1. Differential DNA methylation of sperm
      1. Protection from diet-induced obesity in offspring
  2. Some biological agents like viruses
    1. For example: SARS CoV-2
      1. Positive stranded RNA virus that encodes for four proteins
        Envelope (E)
        Nucleocapsid (N=
        Membrane (M)
        Spike (S)
        It interacts with several host susceptibility factors, in this case, Angiotensin Converting Enzyme 2 (ACE2) receptor
      2. It antagonizes host antigen presentation and activates the interferon pathways through epigenetic modifications
        MERS CoV and SARS CoV use histone methylation and acetylation, DNA methylation and RNA methylation
        It plays with the epigenomic machinery of the host in order to modulate immune response
        Situations like methylation of macrophages DNA can lead to the cytokines storm, the main cause of death by this virus
    2. They inhibit the initiation of the host immune innate response
      1. Age related changes also modify the host epigenome, contributing to this
    3. They modify host metabolism in order to set up a perfect environment for their replication
2. Maternal
  1. Fetal stressors
    1. Maternal food excess and deprivation
    2. Hypoxia
    3. Drug addiction
    4. Alcohol
    5. Emotional Stress
      1. Violence
        Changes in five CpG sites involved in circulatory system processes
      2. Increased cortisol and catecholamines
        Gene expression changes through methylation
        Changes in cerebral blood flow and arterial contractility
    6. They take to developmental programming
      1. From day 0 following fertilization
    7. Obesity
      1. Modifies DNA methylations leading to increased adiposity in offspring
3. Fetal
4. Placental
  1. Important endocrine organ
    1. Maternal stress reduces maternal progesterone concentrations and methylate placental heme oxygenase 1 promoter
      1. It slows fetal growth through immune-related actions
  2. Way of transferring nutrients
5. Nonetheless, it is not only caused by external forces
  1. It is essential in development and it is a natural process
    1. It can be disrupted by the same fetal stressors
      1. For example, the processes can be interfered by deficiency in aminoacids
    2. For example
      1. Complete demethylation of male DNA during fertilization
      2. De novo remethylation for tissue-specific genes to be activated or repressed
Sources (articles): 1. Goyal, D., Limesand, S. W., & Goyal, R. (2019). Epigenetic responses and the developmental origins of health and disease. Journal of Endocrinology, 242(1), T105-T119. 2. Atlante, S., Mongelli, A., Barbi, V., Martelli, F., Farsetti, A., & Gaetano, C. (2020). The epigenetic implication in coronavirus infection and therapy. Clinical epigenetics, 12(1), 1-12. 3. Bird, A. (2007). Perceptions of epigenetics. Nature, 447(7143), 396.
It can happen during the whole life
1. It is not an unique mechanism from humans
  1. Effects seen in rats
    1. Low-protein diet from mothers and its effect in the offspring
      1. Slower rate of cellular proliferation
      2. Hypertension in offspring
        Hypomethylation of the promoter region of the angiotensin-I- converting enzyme and increased ACE mRNA expression in the lung and brain
      3. Altered birth weight
  2. It has had a big relevance throughout the evolution
2. Observation from its effects in pregnancy where most studied in the "Hunger Winter" during the World War II
  1. Famine that caused a higher incidence of cardiovascular disease, type 2 diabetes and mood and personality disorders in people born during it or from women who experienced extreme hunger in it
It represent a profound change in our understanding of genetics
1. The environment does have an effect on genes
  1. "Memory" in genes
    1. Good example: monozygotic twins
2. It is inheritable
Sources (images) https://health.clevelandclinic.org/wp-content/uploads/sites/3/2018/11/obesityDiabCardioDisease-861999778-770x553.jpg https://www.nationalgeographic.com/animals/article/rats-empathy-brains-harm-aversion https://parenting.firstcry.com/articles/identical-monozygotic-twins-all-you-need-to-know/ https://www.renalandurologynews.com/wp-content/uploads/sites/22/2019/02/brainbloodg172591887_1350949.jpg https://www.news-medical.net/image.axd?picture=2019%2F4%2FBy_Design_Cells.jpg https://www.msif.org/wp-content/uploads/2018/08/Double-helix-gene-changes-SM.png https://www.isglobal.org/documents/10179/7759027/Coronavirus+SARS-CoV-2+de+CDC+en+Unsplash/6e5e7633-4ed9-484b-a95f-34195e55e142?t=1584534061000

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Epigenetics

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	Created by Valeria Correa over 3 years ago