{"id":714,"date":"2023-04-03T05:35:29","date_gmt":"2023-04-03T05:35:29","guid":{"rendered":"https:\/\/pressbooks.justwrite.in\/understanding-gene-regulation\/?post_type=chapter&p=714"},"modified":"2023-04-07T10:43:43","modified_gmt":"2023-04-07T10:43:43","slug":"eukaryotic-epigenetic-gene-regulation","status":"publish","type":"chapter","link":"https:\/\/pressbooks.justwrite.in\/understanding-gene-regulation\/chapter\/eukaryotic-epigenetic-gene-regulation\/","title":{"raw":"Eukaryotic Epigenetic Gene Regulation","rendered":"Eukaryotic Epigenetic Gene Regulation"},"content":{"raw":"The DNA and histones that bind the DNA can undergo changes. These changes do not alter the nucleotide sequence and are not permanent, though they often persist through multiple rounds of cell division. These temporary changes can alter the chromosome structure as required.\u00a0<\/span>A gene can be turned on or off depending upon the location and modifications to the histone proteins and DNA.\u00a0<\/span>This type of gene regulation is called epigenetic regulation.<\/span>\r\n

Role of Histones in gene regulation<\/h2>\r\n
\u2022Histone\/nucleosome winding of the DNA molecule may change with the gene activity in a particular cell or tissue.<\/div>\r\n
\u2022When a gene needs to be transcribed but is unavailable because of histone proximity, moving the histone from the DNA strand can free the promoter and associated regulatory sequences so that the sequences are exposed and the\u00a0 gene can be expressed.<\/div>\r\n
\u2022Conversely, if an active gene associated with a nucleosome must be turned off, then moving the DNA so that repressors can attach to the gene's silencers can also be achieved by rewinding the DNA (in the next cell cycle) on the nucleosomes in a different way.<\/div>\r\n

Histone Modifications<\/h2>\r\n
\u2022 Histone modification is a covalent post-translational modification (PTM) to histone proteins.<\/div>\r\n
\u2022 N terminal tails of histone are modified \u00a0by<\/div>\r\n
    \r\n \t
  • \r\n
      \r\n \t
    • methylation,<\/li>\r\n \t
    • phosphorylation,<\/li>\r\n \t
    • acetylation,<\/li>\r\n \t
    • ubiquitylation, and<\/li>\r\n \t
    • sumoylation. (small ubiquitin-related modifier (SUMO) family are conjugated to proteins to regulate such cellular processes as nuclear transport, transcription, chromosome segregation and DNA repair.)<\/li>\r\n<\/ul>\r\n<\/li>\r\n \t
    • Histones modifications is\u00a0 carried out by acetyltransferases and deacetylases, methyltransferases and demethylases.<\/li>\r\n \t
    • The PTMs made to histones can impact gene expression by altering chromatin structure or recruiting histone modifiers.<\/li>\r\n<\/ul>\r\n

      Histone -Lysine acetylation<\/h2>\r\n
        \r\n \t
      • Histone -Lysine acetylation is regulated by two enzymes:<\/li>\r\n \t
      • Histone Acetyltransferases (HATs)<\/strong>\u2013use acetyl-CoA that is specifically recognized and bound by the Arg\/Gln-X-X-Gly-X-Gly\/Ala segment of HATs to transfer an acetyl group to the \u03b5-amino groups on the N-terminal tails of histones .<\/li>\r\n \t
      • Histone Deacetylases (HDACs)<\/strong>\u2013reverses the above modification by HATs<\/li>\r\n \t
      • Lysine acetylation causes a destabilization of the nucleosome and chromatin structure\u2013effectively facilitating access to the DNA for various nuclear factors like the transcription complex.<\/li>\r\n \t
      • Hyperacetylated histones are regarded to be a hallmark of transcriptionally active chromatin.<\/li>\r\n \t
      • The work of HDACs increases the affinity between the nucleosome and the DNA, leading to a closed (heterochromatin-like) chromatin conformation that minimizes accessibility for the transcriptome.<\/li>\r\n<\/ul>\r\n

        Histone methylation<\/h2>\r\n
          \r\n \t
        • This unique posttranslational modification is performed by a specific enzyme family known as the Protein Arginine\u00a0N-Methyltransferases (PRMTs).<\/strong><\/li>\r\n \t
        • \r\n
          Along with serine\/threonine phosphorylation, and lysine methylation and acetylation, arginine methylation is an epigenetic histone modification that regulates gene expression as part of the histone code<\/div><\/li>\r\n<\/ul>\r\n

          Chromatin remodeling<\/h2>\r\n
          \u2022It is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression.<\/div>\r\n
          \u2022When chromatin is tightly packed, and not actively being transcribed it is called heterochromatin.<\/div>\r\n
          \u2022When chromatin is more loosely packed, and therefore accessible for transcription it is called euchromatin.<\/div>\r\n
          \u2022Chromatin remodeling is highly implicated in epigenetics.<\/div>\r\n
          \u2022Epigenetic modifications to histone proteins such as methylation\/demethylation and acetylation\/deacetylation can alter the structure of chromatin resulting in transcriptional activation or repression.<\/div>\r\n
          <\/div>\r\n
          \r\n

          Two classes of chromatin remodeling enzymes<\/strong><\/h2>\r\n
          a) Class I : Histone modifying enzymes<\/strong><\/div>\r\n
            \r\n \t
          • These do not alter nucleosome position<\/li>\r\n \t
          • \u00a0They bring about covalent modification of histone proteins like \u00a0histone tail modifications (Ac, Me, P, Ub, etc.)<\/li>\r\n \t
          • \u00a0Proteins recruited by these modifications include: i)transcription factors ii)ATP-dependent nucleosomal remodeling enzymes iii)histone modifying enzymes<\/li>\r\n<\/ul>\r\n<\/div>\r\n \r\n
            \r\n
            b) Class II : Chromatin remodeling factors<\/strong><\/div>\r\n
            <\/div>\r\n
            \u2022It shifts nucleosome position with respect to DNA, exposing regulatory sequences.<\/div>\r\n
            \u2022These are often referred to as Swi\/Snf factors<\/strong> (because they were first identified as yeast mutants defective in mating type switching and in the ability to metabolize sucrose , sucrose non-fermenting).<\/div>\r\n
            \r\n
            \u2022Chromatin remodeling factors use energy from ATP hydrolysis to rearrange the packing of nucleosomes in higher order chromatin structures.<\/div>\r\n
            \u2022Remodeling improves access to DNA or histone binding sites recognized by transcriptional regulators or histone modifiers.<\/div>\r\n
            \u2022 Some of these bind to :<\/div>\r\n
              \r\n \t
            • \r\n
                \r\n \t
              • \u00a0Activation domains and de-condense the associated chromatin.<\/li>\r\n \t
              • Repression domains and condense the associated chromatin.<\/li>\r\n<\/ul>\r\n<\/li>\r\n<\/ul>\r\n
                \r\n
                \r\n
                \r\n

                DNA Methylation<\/strong><\/h2>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n
                \r\n
                \r\n
                \r\n
                  \r\n \t
                • DNA methylation is the process of adding methyl tags to the bases of the DNA<\/span><\/li>\r\n \t
                • This reaction is carried out by enzymes called\u00a0DNA Methyl Transferases (DMTs)<\/strong><\/span><\/li>\r\n \t
                • The cytosine and Guanine bases of the DNA are more frequently methylated<\/span><\/li>\r\n \t
                • The cytosine \/ guanine rich regions of the genes are called\u00a0CpG Islands<\/strong><\/span><\/li>\r\n \t
                • DNA methylation in the promoter \u00a0regions can repress Gene transcription as it interferes with the binding of transcription factors<\/strong><\/span><\/li>\r\n<\/ul>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n

                  <\/p>","rendered":"

                  The DNA and histones that bind the DNA can undergo changes. These changes do not alter the nucleotide sequence and are not permanent, though they often persist through multiple rounds of cell division. These temporary changes can alter the chromosome structure as required.\u00a0<\/span>A gene can be turned on or off depending upon the location and modifications to the histone proteins and DNA.\u00a0<\/span>This type of gene regulation is called epigenetic regulation.<\/span><\/p>\n

                  Role of Histones in gene regulation<\/h2>\n
                  \u2022Histone\/nucleosome winding of the DNA molecule may change with the gene activity in a particular cell or tissue.<\/div>\n
                  \u2022When a gene needs to be transcribed but is unavailable because of histone proximity, moving the histone from the DNA strand can free the promoter and associated regulatory sequences so that the sequences are exposed and the\u00a0 gene can be expressed.<\/div>\n
                  \u2022Conversely, if an active gene associated with a nucleosome must be turned off, then moving the DNA so that repressors can attach to the gene’s silencers can also be achieved by rewinding the DNA (in the next cell cycle) on the nucleosomes in a different way.<\/div>\n

                  Histone Modifications<\/h2>\n
                  \u2022 Histone modification is a covalent post-translational modification (PTM) to histone proteins.<\/div>\n
                  \u2022 N terminal tails of histone are modified \u00a0by<\/div>\n
                    \n
                  • \n
                      \n
                    • methylation,<\/li>\n
                    • phosphorylation,<\/li>\n
                    • acetylation,<\/li>\n
                    • ubiquitylation, and<\/li>\n
                    • sumoylation. (small ubiquitin-related modifier (SUMO) family are conjugated to proteins to regulate such cellular processes as nuclear transport, transcription, chromosome segregation and DNA repair.)<\/li>\n<\/ul>\n<\/li>\n
                    • Histones modifications is\u00a0 carried out by acetyltransferases and deacetylases, methyltransferases and demethylases.<\/li>\n
                    • The PTMs made to histones can impact gene expression by altering chromatin structure or recruiting histone modifiers.<\/li>\n<\/ul>\n

                      Histone -Lysine acetylation<\/h2>\n
                        \n
                      • Histone -Lysine acetylation is regulated by two enzymes:<\/li>\n
                      • Histone Acetyltransferases (HATs)<\/strong>\u2013use acetyl-CoA that is specifically recognized and bound by the Arg\/Gln-X-X-Gly-X-Gly\/Ala segment of HATs to transfer an acetyl group to the \u03b5-amino groups on the N-terminal tails of histones .<\/li>\n
                      • Histone Deacetylases (HDACs)<\/strong>\u2013reverses the above modification by HATs<\/li>\n
                      • Lysine acetylation causes a destabilization of the nucleosome and chromatin structure\u2013effectively facilitating access to the DNA for various nuclear factors like the transcription complex.<\/li>\n
                      • Hyperacetylated histones are regarded to be a hallmark of transcriptionally active chromatin.<\/li>\n
                      • The work of HDACs increases the affinity between the nucleosome and the DNA, leading to a closed (heterochromatin-like) chromatin conformation that minimizes accessibility for the transcriptome.<\/li>\n<\/ul>\n

                        Histone methylation<\/h2>\n
                          \n
                        • This unique posttranslational modification is performed by a specific enzyme family known as the Protein Arginine\u00a0N-Methyltransferases (PRMTs).<\/strong><\/li>\n
                        • \n
                          Along with serine\/threonine phosphorylation, and lysine methylation and acetylation, arginine methylation is an epigenetic histone modification that regulates gene expression as part of the histone code<\/div>\n<\/li>\n<\/ul>\n

                          Chromatin remodeling<\/h2>\n
                          \u2022It is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression.<\/div>\n
                          \u2022When chromatin is tightly packed, and not actively being transcribed it is called heterochromatin.<\/div>\n
                          \u2022When chromatin is more loosely packed, and therefore accessible for transcription it is called euchromatin.<\/div>\n
                          \u2022Chromatin remodeling is highly implicated in epigenetics.<\/div>\n
                          \u2022Epigenetic modifications to histone proteins such as methylation\/demethylation and acetylation\/deacetylation can alter the structure of chromatin resulting in transcriptional activation or repression.<\/div>\n
                          <\/div>\n
                          \n

                          Two classes of chromatin remodeling enzymes<\/strong><\/h2>\n
                          a) Class I : Histone modifying enzymes<\/strong><\/div>\n
                            \n
                          • These do not alter nucleosome position<\/li>\n
                          • \u00a0They bring about covalent modification of histone proteins like \u00a0histone tail modifications (Ac, Me, P, Ub, etc.)<\/li>\n
                          • \u00a0Proteins recruited by these modifications include: i)transcription factors ii)ATP-dependent nucleosomal remodeling enzymes iii)histone modifying enzymes<\/li>\n<\/ul>\n<\/div>\n

                             <\/p>\n

                            \n
                            b) Class II : Chromatin remodeling factors<\/strong><\/div>\n
                            <\/div>\n
                            \u2022It shifts nucleosome position with respect to DNA, exposing regulatory sequences.<\/div>\n
                            \u2022These are often referred to as Swi\/Snf factors<\/strong> (because they were first identified as yeast mutants defective in mating type switching and in the ability to metabolize sucrose , sucrose non-fermenting).<\/div>\n
                            \n
                            \u2022Chromatin remodeling factors use energy from ATP hydrolysis to rearrange the packing of nucleosomes in higher order chromatin structures.<\/div>\n
                            \u2022Remodeling improves access to DNA or histone binding sites recognized by transcriptional regulators or histone modifiers.<\/div>\n
                            \u2022 Some of these bind to :<\/div>\n
                              \n
                            • \n
                                \n
                              • \u00a0Activation domains and de-condense the associated chromatin.<\/li>\n
                              • Repression domains and condense the associated chromatin.<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n
                                \n
                                \n
                                \n

                                DNA Methylation<\/strong><\/h2>\n<\/div>\n<\/div>\n<\/div>\n
                                \n
                                \n
                                \n
                                  \n
                                • DNA methylation is the process of adding methyl tags to the bases of the DNA<\/span><\/li>\n
                                • This reaction is carried out by enzymes called\u00a0DNA Methyl Transferases (DMTs)<\/strong><\/span><\/li>\n
                                • The cytosine and Guanine bases of the DNA are more frequently methylated<\/span><\/li>\n
                                • The cytosine \/ guanine rich regions of the genes are called\u00a0CpG Islands<\/strong><\/span><\/li>\n
                                • DNA methylation in the promoter \u00a0regions can repress Gene transcription as it interferes with the binding of transcription factors<\/strong><\/span><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

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