Epigenetics is the study of heritable changes in gene function that do not involve changes in the DNA sequence. A variety of epigenetic mechanisms can be perturbed in different types of cancer. Epigenetic alterations of DNA repair genes or cell cycle control genes are very frequent in sporadic (non-germ line) cancers, being significantly more common than germ line (familial) mutations in these sporadic cancers.
Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein–protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants.
Introduction to Cancer
Stem cells and cancer cells
major pathways that lead to formation of tumors.
Tumor Supressors
Colon cancer to prove Knudson hypothesis.
The modern treatments available to treat cancer.
Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein–protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants.
Introduction to Cancer
Stem cells and cancer cells
major pathways that lead to formation of tumors.
Tumor Supressors
Colon cancer to prove Knudson hypothesis.
The modern treatments available to treat cancer.
Introduction
Definition
History
Two hit hypothesis
Functions
Mutation in tumor suppressor genes
What is mutation
Inherited mutation of TSGs
Acquired mutation of TSGs
What is Oncogenes?
TSGs and Oncogenes : Brakes and accelerators
Stop and go signal
Examples of TSGs:
RB-The retinoblastoma gene
P53 protein
TSGs &cell suicide
Conclusion
References
Introduction
Definition
History
Two hit hypothesis
Functions
Mutation in tumor suppressor genes
What is mutation
Inherited mutation of TSGs
Acquired mutation of TSGs
What is Oncogenes?
TSGs and Oncogenes : Brakes and accelerators
Stop and go signal
Examples of TSGs:
RB-The retinoblastoma gene
P53 protein
TSGs &cell suicide
Conclusion
References
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15
years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we
present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it
is time to embrace the central role of epigenetics in cancer.
Next-Generation Sequencing Clinical Research Milestones InfographicQIAGEN
DNA mutations have been implicated in several diseases, particularly cancer. NGS presents an ideal technology to efficiently profile the multitude of mutations in a high throughput manner. In 2001 the first draft of human genome was published. Since then many major milestones have been reached. Do you know when PIK3CA was identified in colon cancer? When was Olaparib for ovarian cancer treatment? This infographic traces the major clinical research milestones starting from the first draft of the human genome.
Unfortunately several cancers are not predictable with simple tests .pdfaquastore223
Unfortunately several cancers are not predictable with simple tests rather required much
intensive diagnosis. The whole genome sequence in determining the entire DNA in normal cells
as well as in tumor cells provide the facility to compare and pin point the mutations occurring in
the oncogenes or tumor suppressor genes responsible for causing the cancer seems to be a better
approach. But such approaches are highly expensive and require expertise.
Though, the whole genome sequencing is carried out pin pointing of specific driver mutations
responsible for cancer phenotype would be a question. Some critical mutations can be identified
in some cancer genome sequences while others are hard to find among the thousands of
possibilities. The mutations like missense, nonsense frameshift, rearrangements may alter the
coding sequences of any gene must be checked. The regulatory mutations that increase the
transcription of oncogenes or decrease that of tumor suppressor genes are potentially important
but are very difficult to find in a whole genome sequence.
The catalogs of regulatory elements in human genomes provide list of certain potential
sequences to be targeted. But the catalogs are rudimentary or incomplete. Therefore, the whole
genome sequencing is not a panacea that will lead to immediate cures of all cancers. Recent
studies have shown that the whole genome sequences of cells derived from different regions of
same tumor have suggested an important reason for cancer reference. Certain cancers are
heterogenous and cells within the tumor have different genomes. Certain mutations in oncogens
or tumor suppressor genes are common to all cells in the tumor but some are not.
These findings make a sense that accumulation of mutations in clone of cells cause cancer.
Therefore, designing drug targeting specific cells protecting adult stem cells cannot be
accomplished. Thus, effective cancer treatments would be directed against the common
mutations but is difficult to identify the specific mutations without sequencing of genomes of
many cells throughout the tumor. Cancer landscape is a large scale cancer genome sequencing
project (cancer genome atlas) funded by National Institute of Health (NIH). In this project the
whole genomes or exomex of several hundreds of cancer are being characterized. The recurrent
patterns of mutations are subdivided cancers in to groups with probable clinical relevance.
For example, 4 groups of breast cancers have been identified. Almost 178 lung squamous cell
carcinoma’s genomes have been characterized and matched with DNA of normal cells from
same patients. Mutations in certain tumor suppressor genes like p53 and certain oncogenes have
shown relatively high frequencies among these cancers. The mutations of certain cancers
resemble cancers in some other organs. For example, pattern of mutation in breast cancer
resembles many ovarian cancers more than other types of breast cancers. These findings may
help in designing the drugs .
ONCOGENE AND PROTOONCOGENE
P53 GENE AND ITS APPLICATION IN CANCER ETIOLOGY
TUMOUR SUPPRESSOR GENE AND BCA AND BAC GENE AND ITS APPLICATION ON THE APOPTOSIS AND DEATH RECEPTORS
h. What are epigenetic changes How may these contribute to the deve.pdfmichardsonkhaicarr37
h. What are epigenetic changes? How may these contribute to the development of cancer?
Describe the mechanism by which methylation of -G-C- sites may contribute to the formation of
cancerous cells. i. What are the six hallmarks of cancer, and what enabling trait allows cells to
acquire the six hallmarks?
Solution
Ques-1: What are epigenetic changes? How may these contribute to the development of cancer?
Epigenetic inheritance can be defined as the process in which complete heritable phenotypic
individual is resulted from chromosomal alterations but there will be no more changes in the
DNA sequence followed by differential gene expression of the phenotype. Recent research has
illustrated that epigenetic inheritance is involves both mitotically and meiotically. However,
mitotic or somatic inheritance is higher because of no reprogramming events of altered
chromatin. In meiosis for gametogenesis, a lot of reprogramming events to repair \"alterations in
chromatic\" has involved for altered cpG islands in both sperm cells and oocytes result in no
inheritance propagation from generation to generation. For instance, Epigenetic alterations can
be produced due to the exposure to the environment, in case of mice; dietary nutritional additives
can induce gene express of agouti gene, further result in the improper fur color and increased
level of cancer growth.
Ques-2: Describe the mechanism by which methylation of -G-C- sites may contribute to the
formation of cancerous cells.
Epigenetic changes in chromatin structure that affects gene expression. The epigenetic changes
involves in the viable gene expression inside the cells due to methylated -G-C- sites on DNA
with differential pattern finally silencing of large number of genes approximately 550 genes
(CpG dinucleotides) chemically methylated and modified to change the gene expression. These
events are leading to generation of abnormal phenotypes of cells finally become neoplastic &
undergoes metastasis
Que-3: What are the six hallmarks of cancer, and what enabling trait allows cells to acquire the
six hallmarks?
Invasion is mainly due to presence of cell adhesion molecules such as integrins on the cancer
cells finally promote the movement of cancer cells to another region. This process is going to
connect adjacent cells to tumor cells finally undergo epithelial-mesenchymal transition
Intravastation is the process in which cancer cells undergoes metastasis to enter into “blood or
lymph stream” and these cancer cells secrete metalloprotenases, proteases to degrade basement
membrane of the stromal surface for endothelial migration. Sometimes, these cancer cells are
going to promote angiogenesis (synthesis of blood vessels) towards them to obtain nutrients
Extravasation is the process in which cancer cells are going to undergoes metastasis and “escape
from lymphatic vessels or blood vessel” by detaching from endothelium
Six hallmarks of cancer:
Self sufficiency in generating growth signals, insensitivity .
DNA Methylation and Epigenetic Events Underlying Renal Cell Carcinomaskomalicarol
Renal cell carcinoma (RCC) refers to a group of tumors that develop from the epithelium of the kidney tubes, including clear cell
RCC, papillary RCC, and chromophobe RCC. Most clear cell renal
carcinomas have a large histologic subtype, genetic or epigenetic
genetic von Hippel-Lindau (VHL). A comprehensive analysis of
the genetic modification genome suggested that chromosome 3p
loss and chromosome gains 5q and 7 may be a significant copy
defect in the development of clear kidney cell cancer. A more potent renal cell carcinoma may develop if chromosome 1p, 4, 9,
13q, or 14q is also lost. Renal carcinogenesis is not associated with
chronic inflammation or histological changes. However, regional hypermethylation of DNA in CpG C-type islands has already
accumulated in cancer-free kidney tissue, implying that the presence of malignant kidney lesions may also be detected by modified
DNA methylation. Modification of DNA methylation in cancerous
kidney tissue may advance kidney tissue to epigenetic mutations
and genes, leading to more serious cancers and even determining
a patient’s outcome
The sodium channel is a channel present on the membrane that allows a small amount of Na+ to enter the cell along its electrochemical gradient, as discovered by British scientists Hodgkin and Huxley. It can be divided into two types, voltage-gated and ligand-gated. The sodium ion channel is the primary activation bond for electrical signals in all animals, while the electrical signal is the basis for a series of physiological processes such as neural activity and muscle contraction.
Numerous cells are able to ingest foreign materials, but the ability to increase this activity in response to opsonization by antibody and/or complement, so as to acquire antigen specificity, is restricted to cells of the myeloid series, principally polymorphs, monocytes and macrophages; these are sometimes termed ‘professional’ phagocytes.
Neuroscience is characterized by multi-disciplinary and multi-level intersections. It combines behavior, cognition and brain mechanism, and it attempts to elaborate the neural mechanism of human and animal in perceiving objects, forming images, using language, memorizing information, reasoning and decision-making at the micro level of molecule, synapse and neuron and at the macro level of system, whole brain and behavior.
Transient receptor potenital (TRP) is a large family of non-selective cation channels located on the cell membrane. One type of channel can be activated by Vanillic acid compounds, so this type of channel is called the TRPV subfamily. Mutations in TRPV are associated with neurodegenerative diseases, skeletal dysplasia, kidney disease and cancer and TRPV is an important therapeutic target for these diseases.
CFTR is a chloride channel located on the cell membrane. Under the mediation of cAMP, CFTR is phosphorylated, causing the channel to open and transporting about 10 CIs extracellularly per minute. When the cftr gene is mutated (most commonly, the codon encoding 508 phenylalanine is lost), the defective CFTR cannot be processed normally in the endoplasmic reticulum, and most cannot be transported to the cell membrane;
The organic cation transporter (OCT) is an important drug delivery protein with a broad tissue distribution in the body that mediates the metabolic processes of most drugs. At present, the gene sequence, transport mechanism, substrate structure specificity, regulatory mechanism, gene polymorphism andin vivodistribution characteristics of this transporter have been deeply studied. Based on this knowledge, pharmacologists have successfully delivered many drugs at the transporter molecule level and applied them to clinical practice.
In genetics, genotoxicity describes the property of chemical agents that damage the genetic information within a cell causing mutations(Genotoxicity is often confused with mutagenicity. All mutagens are genotoxic, whereas not all genotoxic substances are mutagenic.). The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage resulting in mutations.
The process of cell cycle regulation is the activation or inactivation of various regulatory factors under the surveillance of checkpoints, thereby initiating the process of cell DNA replication and division into two daughter cells.
DNA mismatch repair (MMR) recognizes and repairs erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, and repair some forms of DNA damage. It plays an important role in maintaining genomic stability and cellular homeostasis.
Post-translational modifications play an important role in cells, such as DNA recognition, protein-protein interactions, catalytic activity, and protein stability. Protein acetylation/deacetylation is a histone covalent modification that is mainly catalyzed by histone acetylase and histone deacetylase, respectively.
DNA mismatch repair (MMR) recognizes and repairs erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, and repair some forms of DNA damage. It plays an important role in maintaining genomic stability and cellular homeostasis.
Mitochondria are a subcellular structure prevalent in eukaryotic cells and the most important source of energy in cells. Most tissue cells in the human body rely on oxidative phosphorylation of mitochondria to obtain the energy needed to maintain their metabolism.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
1. Cancer Epigenetics
Epigenetics is the study of heritable changes in gene function that do not involve
changes in the DNA sequence. A variety of epigenetic mechanisms can be perturbed
in different types of cancer. Epigenetic alterations of DNA repair genes or cell cycle
control genes are very frequent in sporadic (non-germ line) cancers, being
significantly more common than germ line (familial) mutations in these sporadic
cancers. So researchers think that epigenetic alterations may be just as important, or
even more worthy, than genetic mutations in a cell's transformation to cancer.
So far, the mechanisms of epigenetic is the covalent modifications(covalent
modifications of either DNA (e.g. cytosine methylation(CpG) and hydroxymethylation)
or of histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine
and threonine phosphorylation, and lysine ubiquitination and sumoylation).), RNA
transcripts(include: recruitment of a hierarchy of generic chromatin modifying
complexes and DNA methyltransferases to specific loci; the production of different
splice forms of RNA; formation of double-stranded RNA (RNAi)), MicroRNAs, the
modification of mRNA, sRNAs, Prions and so on. In cancers, loss of expression of
genes occurs about 10 times more frequently by transcription silencing (caused by
epigenetic promoter hypermethylation of CpG islands) than by mutations.
As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6
driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon
tumors compared to adjacent normal-appearing colonic mucosa, there are about 600
to 800 heavily methylated CpG islands in promoters of genes in the tumors while
these CpG islands are not methylated in the adjacent mucosa. Manipulation of
epigenetic alterations holds great promise for cancer prevention, detection, and
therapy. In different types of cancer, a variety of epigenetic mechanisms can be
perturbed, such as silencing of tumor suppressor genes and activation of oncogenes
by altered CpG island methylation patterns, histone modifications, and dysregulation
of DNA binding proteins. Several medications which have epigenetic impact are now
employed in several of these diseases.
