11-regulacion transcripcion eucariotes i 2011-2

8/4/2019 11-Regulacion Transcripcion Eucariotes I 2011-2

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REGULACIN EXPRESIN EN

EUCARIOTES

Jorge Arevalo

2011


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Regulation of Gene

Activity in

Eucaryotes

1. Transcription2. RNA processing3.

mRNA transport4. mRNA degradationand storage

5. Translation6. Posttranslational

modulation of

protein activity


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Nuclear factorslike NF-B orNFAT are involvedin the activation ofmany differentgenes.

Gene transcriptionis a complicatedprocess whoseregulationinvolves a lot offactors


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El ejemplo muy estudiado: GAL en

levadura


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Regulacin Hormonal


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La heterocromatina en la

regulacion genica


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Chromatin Remember, DNA in

eukaryotes packs intoCHROMATIN.

HISTONES form theNUCLEOSOME, whichDNA loops around.

EUCHROMATIN - lesscompact; activelytranscribed

HETEROCHROMATIN -more compact;transcriptionallyinactive. Heterochromatin can be

either constitutive orfacultative.


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How do Eukaryotic TranscriptionalRegulators Work?

At least one way is by altering the packing of DNA intochromatin.

The role of chromatin structure in the regulation oftranscription is an area of very active investigation.

However, two important factors that play clear roles intranscriptional regulation are known: DNA METHYLATION - A subset of cytosine (C) residues are

modified by methylation.

HISTONE ACETYLATION - Histones can be modified byacetylation.


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DNA Methylation Genes that are transcriptionally inactive are often

METHYLATED.

In eukaryotes, cytosine residues are modified by methylation.

Typically, the sites of methylation are CG dinucleotides(vertebrates). This allows maintenance through replication.!

CYTOSINE

METHYL-C


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Histone Acetylation

HISTONES in transcriptionally active genes are oftenACETYLATED.

Acetylation is the modification of lysine residues inhistones. Reduces positive charge, weakens the interaction with DNA.

Makes DNA more accessible to RNA polymerase II

Enzymes that ACETYLATE HISTONES are recruited toactively transcribed genes.

Enzymes that remove acetyl groups from histones arerecruited to methylated DNA.

There are additional types of histone modification as well,such as methylation of the histones.


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Efectos localizados de modificacin

de la cromatina


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Fig. 4. Model for formation of silenced chromatindomains. After therecruitment to a specific heterochromatin nucleation siteby proteins

that directly bind DNA or are targeted by way of RNAs,histonemodifying

enzymes (E) such as deacetylases andmethyltransferases

modify histone tails to create a binding site for silencingfactors (SF).

After this nucleation step, self-association of silencingfactors (such as

Swi6/HP1 or Sir3) is hypothesized to provide an interfacefor their

interaction with histone-modifying enzymes, which then

modify adjacenthistones, creating another binding site for silencingfactors. Sequentialrounds of modification and binding result in the stepwisespreadingof silencing complexes along nucleosomal DNA forseveral kilobases(spreading). Spreading of silencing complexes is blockedby the presenceof boundary elements (BE). The modifications associatedwith the amino

terminus of histone H3 in fission yeast heterochromatin(bottom left)

and euchromatin (bottom right) are illustrated as anexample. Deacetylation

and methylation of H3 Lys9are followed by deacetylationof H3

Lys14 and create a binding site for the Swi6 silencingfactor.


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REGULACION EPIGENETICA


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Genetic Imprinting

Remember that DNA methylation can be maintainedthrough replication.

This allows the packing of chromatin to be passed on -just like a gene sequence. However, differences in chromatin packing are not as stable as

gene sequences.

Heritable but potentially reversible changes in geneexpression are called EPIGENETIC phenomena

Vertebrates use these differences in chromatin packing toIMPRINT certain patterns of gene regulation.

Some genes show MATERNAL IMPRINTING while other showPATERNAL IMPRINTING.

The alleles of some genes that are inherited from therelevant parent are methylated, and therefore are notexpressed.


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Prader-Willi &Angelman Syndromes

Both of these genetic disorders are caused bydeletion of a region of chromosome 15.

However, the syndromes differ: Prader-Willi Syndrome - obesity, mental retardation,short stature. (abbreviated PWS) Angelman Syndrome - uncontrollable laughter, jerky

movements, and other motor and mental symptoms.(abbreviated AS)

Syndrome that develops depends upon theparent that provided the mutant chromosome.


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PWS

AS

PWS

Mousemodel

ASMousemodel

From Annu Rev Genomics & Hum Genet


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Prader-Willi & Angelman Syndromes

Prader-Willi Syndrome - develops when theabnormal copy of chromosome 15 is inheritedfrom the father.

Angelman Syndrome - develops when theabnormal copy of chromosome 15 is inheritedfrom the mother.

The differences reflect the fact that some lociare IMPRINTED - so only the allele inherited

from one parent is expressed. The region contains both maternally and paternally

imprinted genes.


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Methylation and Gene Regulation

For imprinted genes, the pattern of generegulation is dependent upon the parentthat donated the chromosome.The methylation pattern is reprogrammed

in the germ line. There are other examples of methylation

changes the regulate gene expression.In mammals, one of the two X chromosomes

in females is inactivated.The inactivated X is methylated.

11-regulacion transcripcion eucariotes i 2011-2

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