Revised- Gene regulatiion Eukaryotics.pdf

5
Revised- Gene regulatiion Eukaryotics.pdf


Revised- Gene regulatiion Eukaryotics.pdf

Revised- Gene regulatiion Eukaryotics.pdf

  • 2. Introduction
     Gene regulation
    is a fundamental process that
    allows an organism to control the expression
    of its genes, determining when and to what
    extent specific genes are turned on or off.
     Only a portion of each cell’s genes are
    expressed, or turned on, at any given time.
     The process of turning genes on and off is
    known as gene regulation.
    2
  • 3. Introduction
     In contrast
    to prokaryotes, gene expression in
    eukaryotes is controlled at multiple levels.
     Reason: This can be attributed to the cell
    arctechture of the eukaryotic cell.
     Eukaryotic genes are not organized into
    operons, so each gene must be regulated
    independently
     Regulation of gene expression can happen at
    any of the stages : at DNA packaging,
    Transcription and translation into protein
  • 4. Purpose of gene regulation
     In general :
     Allows the cell to express gene products (protein or
    RNA) only when needed
     By differential expression of genes, cells can respond to
    changes in the environment or adapt to new food
    sources
     Gene regulation drives cellular differentiation and
    morphogenesis in the embryo, resulting in the formation
    of various cell types.
     Differential expression, allows cells to specialize in
    multicellular organisms.
     is an important part of normal development. 4
  • 5. • Cellular Differentiation: Gene regulation
    plays a crucial role in the process of cellular
    differentiation, where cells become
    specialized for specific functions.
    • Response to Environmental Changes:.
    Cells can adjust their gene expression
    patterns in response to external signals, such
    as changes in temperature, nutrient
    availability, or the presence of specific
    molecules
    5
  • 6. Development and Growth:
    Gene regulation is essential for the
    coordinated growth and development of an
    organism.
    • It ensures that genes are activated or
    repressed at specific times and in specific
    tissues, allowing for the proper formation of
    organs, tissues, and structures during
    embryonic development and beyond
    6
  • 7. Cell Cycle Control:
    Genes
    involved in the cell cycle, including
    those regulating cell division and apoptosis,
    are tightly controlled.
    • Proper regulation ensures the accurate
    progression of the cell cycle, preventing
    abnormal cell growth, and maintaining
    genomic stability.
    7
  • 8. Energy Conservation:
     Gene
    regulation helps conserve energy by
    ensuring that cells only produce the proteins
    they need at a given time.
     Unnecessary protein synthesis can be
    energetically costly, and gene regulation
    helps optimize resource allocation within
    the cell.
    8
  • 9. Level of gene regulation
     epigenetic,
     transcriptional,
     post-transcriptional
     translational
     post-translational
    9
  • 11. DNA Packaging
     Each
    chromosome contains a single DNA molecule that
    extends from one end to the other.
     DNA is coiled around a protein( histones) to form nucleosomes
     A “chromatin” is formed when a DNA molecule is coiled and
    folded multiple times with associated proteins.
     The chromosomal proteins are divided into Histone proteins
    and Non-Histone proteins.
     Histone proteins are positively charged and have several arginine
    and lysine amino acids that bind to the negatively charged
    DNA. Histones are of two types:
     Core Histones (H2A, H2B, H3 and H4)
     Linker Histones (H1)
    11
  • 13. The Normal Human Chromosomes
    • Normal human cells contain 23 pairs of homologous
    chromosomes ie 22 pairs of autosomes and 1 pair of sex
    chromosomes.
    • Sex chromosomes are XX in females and XY in males.
    • Both X are homologous. Y is much smaller than X and
    has only a few genes
    • Therefore, Mammalian females inactivate one X
    chromosome as a form of dosage compensation to
    equalize X-chromosome expression in both sexes.
    13
  • 14. Epigenetic Mechanisms of Gene Regulation
    • epigenetics is the study of heritable
    changes in gene expression that occur
    without a change in the primary DNA
    sequence of an organism.
    • Epigenetics: Occurs when a chemical
    compound or protein attaches to the gene
    and alters gene expression. The DNA
    sequence is not changed.
    14
  • 15. Epigenetic Mechanisms of Gene Regulation
     Epigenetic regulation is mainly executed by DNA
    methylation and histone modification
     Chromatin Structure Affects Gene Expression
    Euchromatin: Loosely packed DNA
    Heterochromatin: tightly packed form of DNA
    or condensed DNA
     Chromatin structure is affected by a wide variety
    of modifications to histones as well as DNA
    methylation
    15
  • 16. DNA methylation
     DNA
    methylation was the first modification of
    chromosome structure shown to act epigenetically.
     The addition of a methyl group to cytosine by a
    methylase enzyme creates 5-methylcytosine, but
    this change has no effect on its base-pairing with
    guanine.
     Methylation is a way of marking genes for
    silencing
     High levels of DNA methylation correlate with
    inactive genes, and the allele specific gene
    expression seen in genomic imprinting is mediated
    16
  • 17. • 5-Methyl-cytosine is the only modified base
    commonly found in eukaryotes.
    Caenorhabditis elegans, Drosophila, and
    yeast, however, contain little or no 5-
    methyl-cytosine
    17
  • 18. Cont..
    18
    DNA methylation. Cytosine
    is methylated, creating 5-methylcytosine.
    Because the methyl group (green) is positioned to the side, it does not
    interfere with the hydrogen bonds of a G–C base-pair, but it can be
    recognized by proteins.
  • 19. Histone modification
     Histones
    are chromosomal proteins that tightly wind
    DNA so that it fits into the nucleus of a cell.
     If a gene is to be transcribed, the nucleosomes around
    DNA can slide down to open that specific chromosomal
    region and allow access for RNA polymerase and other
    proteins, to bind to the promoter region and initiate
    transcription.
     Conversely, in closed configuration, the RNA
    polymerase and transcription factors do not have access to
    the DNA and transcription cannot occur
    19
  • 20. Cont…
    20
     Since DNA
    negatively charged, changes in
    the charge of the histone will change how
    tightly wound the DNA molecule will be.
     Histone Modifications include acetylation
    and methylation of lysine; and
    phosphorylation of serine, threonine, and
    tyrosine
  • 21.  Addition of phosphate, methyl, or acetyl groups
    acts at signal tags that open or close a
    chromosomal region
     E.g acetylation, especially of H3, is correlated
    with active sites of transcription, both in
    regulatory regions and in the transcribed region
    of the gene itself.
     While methylation of the same histone (H3)
    can have the opposite effect, depending on the
    lysine methylated.
    21
  • 22. Cont…
    22
    A) When nucleosomes
    are spaced closely together, transcription
    factors cannot bind and gene expression is turned off. (B) When
    nucleosomes are spaced far apart, transcription factors can bind,
    allowing gene expression to occur.
  • 23. Transcriptional Control of Gene Expression
    • Transcriptional regulation is control of whether or
    not an mRNA is transcribed from a gene in a
    particular cell.
    • In eukaryotes, RNA polymerase alone cannot initiate
    transcription as it requires other proteins, or
    transcription factors, to facilitate transcription
    initiation
    • Transcription factors are proteins that bind to the
    promoter sequence and other regulatory sequences
    to control the transcription of the target gene
    23
  • 24. cont…
     Transcriptional factors
    can be general transcription
    factors and specific transcription factors.
     General factors are necessary for the assembly of a
    transcription apparatus and recruitment of RNA
    polymerase II to a promoter. Eg Transcription factor
    RNA polymerase II (TFII).
     Specific factors increase the level of transcription in
    certain cell types or in response to signals.
    24
  • 25. Structure of a Eukaryotic gene
    Exons – Coding
    Introns – Non coding
    Promoter – Essential for transcription
    Enhancer – modulates the rate of transcription
    TATAA –Basal transcription complex
    CAAT – NF1
    GC – Sp1
    Oct – Octamer binding protein
    INR – Binds subunits of TFIID
    EXON 1 EXON 2 EXON 3
    Intron 1 Intron 2
    TATAA
    Promoter
    Poly-adenylation
    signal
    ~100bp
    Enhancer
    Start site for
    transcription
    CAAT
    GC
    Oct
    INR
  • 26. Promoter
     the promoter
    region is immediately upstream of the
    coding sequence. This region can range from a few to
    hundreds of nucleotides long.
     The purpose of the promoter is to bind transcription
    factors that control the initiation of transcription
     Within the promoter region, resides the TATA box
    which is a repeat of thymine and adenine dinucleotides
    which binds transcription factors to assemle an
    initiation complex.
  • 28. Enhancers and Repressors
    Enhancers are binding sites for activators and in
    some eukaryotic genes, there are regions that
    help increase transcription.
     Transcriptional repressors can bind to promoter
    regions and block transcription
    28
  • 29. Post-transcriptional Control of Gene Expression
     Post-transcriptional regulation occurs after the
    mRNA is transcribed but before translation
    begins.
     This regulation can occur at the level of mRNA
    processing, transport from the nucleus to the
    cytoplasm, or binding to ribosomes.
    29
  • 30. Alternative RNA splicing
    Post-transcriptional regulation occurs after the
    mRNA is transcribed but before translation begins
     when introns are removed from the primary RNA
    transcript by RNA splicing, the remaining exons
    are spliced together to generate the final, mature
    mRNA
     Alternative RNA splicing is a mechanism that
    allows different combinations of introns, and
    sometimes exons, to be removed from the primary
    transcript
    30
  • 32. CONT…
     The lenghth
    mRNA , and its poly-A tail are
    important for mRNA
     the binding of RNA-binding proteins (RBP) to pre
    RNA can increase or decrease the stability of an
    RNA molecule, depending on the specific RBP that
    binds.
     The microRNAs, or miRNAs, can also bind to the
    RNA molecule and further degrade i.
    32
  • 33. microRNAs, or miRNAs
    miRNAs are short (21–24 nucleotides) RNA molecules that
    are made in the nucleus and then chopped into mature
    miRNAs by a protein called dicer.
     Produced miRNA is loaded into a complex of proteins
    called an RNA-induced silencing complex, or RISC.
     The RISC includes the RNA-binding protein Argonaute
    (Ago), which interacts with the miRNA.
     One of the the complementary strand is removed by
    nucleases enzymes
     The the RISC is targeted to repress the expression of other
    genes based on sequence complementarity to the miRNA
     the other RNAs are vital to the process of gene silencing
    and participate in the mechanism of gene regulation, referred
    to as RNAi or RNA interference
    33
  • 34. Translational Control of Gene Expression
     Translation can also be regulated at the level of
    binding of the mRNA to the ribosome.
     Ribosomes are found in cytoplasme and on the
    endoplasmic reticulum (ER).
     Proteins destined to ER , use a signal sequence for
    their transportation to ER and translation
    resumes from there
    34
  • 35. Post-translational Control of Gene Expression
     This type of control entails altering the protein after
    it has been created in order to change its activity.
     enzyme inhibition
     The activity and/or stability of proteins can also be
    regulated by adding functional groups, such as
    methyl, phosphate, or acetyl groups.
     tagged proteins for degradation are moved to a
    proteasome, an organelle that degrades proteins
    35
  • 36. Genomic imprinting
    • Genomic
    imprinting is an epigenetic
    phenomenon that results in the expression
    of genes in a parent-of-origin-specific
    manner.
    • In other words, the expression of certain
    genes depends on whether they are
    inherited from the mother or the father.
    36
  • 37. • Cells normally have two copies, or “alleles,”
    of autosomal genes on chromosomes other
    than the X and Y.
    • One allele is inherited from the mother
    (maternal allele) and one is inherited from the
    father (paternal allele).
    • For most genes, both copies are expressed by
    the cell.
    • A small class of genes shows “monoallelic”
    expression
    37
  • 38. • In genomic imprinting, selection of the active
    allele is nonrandom and based on the parent of
    origin
    • For example, a gene that is imprinted to be
    expressed only when inherited from the father
    will be silent if inherited from the mother, and
    vice versa.
    • Genomic imprinting affects a small subset of
    genes and results in the expression of
    • those genes from only one of the two parental
    chromosomes.
    38
  • 39. Examples of genomic imprinting in humans is
    the gene
    • One well-known example of genomic
    imprinting in humans is the gene for insulin-
    like growth factor 2 (IGF2), which is only
    expressed when inherited from the father,
    while the maternal copy is silenced.
    • Conversely, another gene called H19, located
    adjacent to IGF2, is expressed only when
    inherited from the mother, with the paternal
    copy being silenced.
    39
  • 40. Genomic imprinting and neurodevelopmental
    disorders
    • Three neurodevelopmental disorders,
    Prader–Willi syndrome,
    • Angelman syndrome, and Rett syndrome
    (all named after the physicians who first
    described the disorders), are the result of
    either direct or indirect deregulation of
    imprinted genes.
    40


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