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T87dha3orwynsetk0zyh 180522 s0 hashmi uzair epigenetics intro
05:18
Epigenetics
Nfnhvtdnqclikiickz5y 180522 s1 hashmi uzair epigenetic control
13:11
Epigenetic Control
Oxpf3qfqrrq68a1tq01t 180522 s2 hashmi uzair targeting epigenetic changes in cancer
12:31
Targeting Epigenetic Changes in Cancer
7m2tmp87rgmocf2t1tqb 180522 s3 hashmi uzair role of epigenetic players in cancer progression
12:58
Role of Epigenetic Players in Cancer Progression
Cpmso6yq9wf662o0ceab 180522 s4 hashmi uzair epigenetic changes during stem cell differentiation
14:35
Epigenetic Changes During Stem Cell Differentiation
Mpwkz4btkqm9kzhauyko 180522 s5 hashmi uzair epigenetics and arterial diseases
06:16
Epigenetics and Arterial Diseases

Lecture´s Description

Epigenetic Control

In the early years, cytologists used various chromatin dyes and DNA-binding fluorochromes to discriminate euchromatic from heterochromatic regions in eukaryotic chromatin. In 1996, the nuclear histone acetyltransferase (HAT) p55 from Tetrahymena thermophila was described as a transcriptional co-activator that acetylates the histone H3 amino-terminal tail. The acetylated (Ac) lysine on H3 (H3K14ac) provides a docking site for bromodomain (Bromo)-containing accessory proteins that bind to and further stimulate nucleosome accessibility and transcriptional activity. Histone acetylation can be reversed by opposing histone deacetylases (HDACs), which often cause transcriptional repression. A chromatin template has chief mechanisms, such as:

  • Histone modifications
  • DNA methylation
  • Histone variants and remodelling
  • Non-coding RNA, that alter chromatin structure and function in an inter-dependent fashion.

Distinct adaptations of this chromatin template have been associated with various functions of the epigenome. Pharmacological intervention and possible reversal of dysregulated epigenetic control by small-molecule inhibitors (epigenetic therapy) for example, histone deacetylase inhibitors (HDACi) or DNA methylation inhibitors (DNMTi)) or metabolic co-factors for example, α-ketoglutarate (α‑KG)) are described. Many of these treatments with epigenetic inhibitors have been shown to ameliorate disease in some clinical settings, some are still at an exploratory stage.

Targeting Epigenetic Changes in Cancer

In human cancers, epigenetic mutations may lead to at least four major phenotypes:

  • DNA promoter hypermethylation
  • Genome‑wide DNA hypomethylation
  • Abnormal histone modifications and binding of their readers
  • Abnormal chromatin structures.

Histone methyltransferases (HMTs) and histone demethylases (HDMs) that are mutated or overexpressed in cancers with their corresponding inhibitors are shown. HMT inhibitors bind within the S‑adenosylmethionine (SAM) pocket, within the substrate pocket or within the allosteric sites. KDM1A, a flavin-dependent HDM, is inhibited by molecules that covalently modify the FAD cofactor, and KDM1A inhibitors. Epigenetic inhibitors also have an important role in immuno‑oncology. Three classes of epigenetic inhibitors are currently in clinical trials, in combination with either a blockade of programmed cell death protein 1 (PD1)–programmed cell death 1 ligand 1 (PDL1) interaction or blockade of cytotoxic T lymphocyte antigen 4 (CTLA4).  Owing to their roles in transcriptional regulation, DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors upregulate the expression of the antigen-presenting major histocompatibility complex (MHC) molecules, tumour antigens, and T helper 1 (TH1)-type chemokines CXC-motif chemokine ligand 9 (CXCL9) and CXCL10.

Role of Epigenetic Players in Cancer Progression

Ageing, inflammation and chronic exposure to carcinogens impinge on epigenetic modulators, such as adenomatous polyposis coli (APC) and signal transducer and activator of transcription 3 (STAT3), that fine tune and regulate the function of epigenetic modifiers. For example, TET methyl cytosine dioxygenase 2 (TET2) and AT-rich interaction domain 1A (ARID1A) to bring about changes in the expression of epigenetic mediators.   Sex-determining Y-box 2 (SOX2) and OCT4-whose gene products regulate developmental potential. Chronic exposure to a fluctuating, cancer-predisposing environment and ageing promote the selection for epigenetic heterogeneity in vulnerable populations of somatic stem cells and progenitor compartments. The mechanism of epigenetic instability involves the erosion of barriers against dedifferentiation, such as large organized chromatin K9 modifications (LOCKs) overlapping with lamina-associated domains (LADs), and the emergence of hypomethylated blocks that contain the most variably expressed domains of the tumour genome and interfere with normal differentiation. This hypothetical scheme explains how epigenetic mediators (for example, OCT4) might reprogramme the epigenome to tip over normal somatic stem cells or differentiated progenitor cells into cancer stem cell states displaying phenotypic heterogeneity. The Waddington landscape of development is adapted to compare cellular states of different entropy during normal differentiation and in cancer. The developmental potential of normal somatic stem cells positioned on the top of the hill correlates with high entropy, which is mediated by cellular heterogeneity. During differentiation, cells are guided towards well-defined cell fates with lower entropy, paralleled by a decrease in transcriptional noise and the stabilization of cell states.

Epigenetic Changes During Stem Cell Differentiation

After fertilization, the zygote undergoes consecutive rounds of cleavage to generate the blastocyst which consists of two major cell types:

  • The pluripotent cells
  • The trophoblast cells

The pluripotent inner cell mass (ICM) cells that give rise to all cell lineages and the trophoblast cells that form the extra-embryonic placenta. At later blastocyst stages, ICM cells undergo a second round of cell commitment to generate the pluripotent epiblast cells and the overlying hypoblast layer. During post-implantation development, primed epiblast cells exit pluripotency and undergo lineage commitment to generate different somatic cell types. Conventional ESCs that are derived from mouse pre-implantation embryos are maintained in culture conditions supplemented with serum and leukaemia-inhibitory factor(LIF). Lamina-associated domains are marked by histone H3 lysine 9 dimethylation (H3K9me2) or trimethylation (H3K9me3) and are positioned close to the nuclear membrane. Topologically associated domains (TADs) can acquire different epigenetic modifications and switch between more active compartments or less active compartments. TAD organization is mostly stable between different cell types but sub-TAD organization change depending on the extent of differentiation and epigenetic modifications. Enhancer-promoter sub-TAD loops are mediated by different transcription factors. Enhancer activation is initiated by binding of pioneer transcription factors that increase the chromatin accessibility and generate a permissive chromatin environment for other transcription factors and epigenetic modifiers to bind.  In serum-cultured embryonic stem cells (ESCs) and epiblast-derived stem cells, a high level of 5-methylcytosine DNA methylation restricts trimethylation of histone H3 at lysine 27 (H3K27me3) deposition to CpG-rich bivalent promoters. In ground-state ESCs, global DNA demethylation leads to carpeting of the genome by H3K27me3 and reduced H3K27me3 deposition at bivalent promoters.

Epigenetics and Arterial Diseases

There are three key epigenetic mechanisms that regulate gene expression:

  1. 1. Methylation of CpG islands, mediated by DNA methyltransferases
  2. 2. Histone protein modifications
  3. 3. MicroRNAs.

The various epigenetic modifications control gene activation and silencing affecting gene expression. Relevance of epigenetic marks to the effect and response to ischaemic injury is represented by a simplified diagram highlighting the different types of epigenetic marks and the complexity of various epigenetic gene regulation mechanisms and the cell types involved in ischaemic injury development and resolution.  A number of risk factors common to both CVD and PAD have been identified to cause epigenetic changes. Epigenetic alterations influence common pathologic responses including inflammation, ischaemia, hypoxia and shear stress. Risk factors, such as diabetes and life style habits such as smoking, modulate the epigenome promoting maladaptive changes.

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