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Module 11(1-2) - March 26-28 - BIO 2C03.docx

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Joe Kim

BIO 2C03 2013 Module 11 Lecture 1 – X Chromosome Inactivation (March 26) X-Inactivation and Imprinting Share Several Features  Genes affected by X Inactivation or Imprinting are expressed from a single allele as a result of silencing of the second allele  X Inactivation – a whole chromosome is selected and inactivated  Imprinting – one of two alleles is silenced depending on whether it is inherited from the mother or the father  Genes affected by these processes tend to be clustered  In both processes, o Silencing depends on a “master control region” o lncRNAs act as master regulators of silencing  X-inactivation and imprinting regulate 5-10% of the genes of the genome  Several diseases are determined by genes controlled by X Inactivation or Imprinting o Rett syndrome (X-linked disorder) o Fragile X (X-linked disorder) o Hemophilia (X-linked disorder) o Testicular Feminization (X-linked disorder) o Prader-Willi/Angelman (due to Imprinting) o Backwith-Widemann (due to Imprinting) X-Inactivation – Why?  Females – 2 X chromosomes – two copies (doses) of each gene  Males – 1 X chromosome – one copy (dose) of each gene  Inactivating one of the two X chromosomes in females compensates for this imbalance  Dosage Compensation – way of equalizing gene expression in the face of different gene dosage o Can occur in one of a number of ways  Increasing expression from the single X-chromosome (in males)  Decreasing expression from the two X chromosomes  Turning off expression from one X chromosome (in females) o While mechanisms vary, all involve modifications to chromosome structure and gene expression, including histone modification o Dosage compensation is an example of epigenetic phenomenon – a heritable change in gene expression that does not involve a change in DNA sequence  Brief History o Interphase nucleus – female cell  Yellow = fluorescent probe that recognizes the X chromosome o Condensed mass in nucleus of female cells in cats, not male (Murray Barr and Ewart Bertram, 1949) o Proposed that the mass was the X chromosome (Susumu Ohno, 1960 ) o X condensation results in silencing of the whole chromosome (Mary Lyon, 1961)  Early in development, one X chromosome is inactivated in each cell – the process is random; equally likely that the maternal or paternal X chromosome will be inactivated  All descendent cells maintain the inactivation pattern  Figure – all descendent cells are expressing b allele phenotype = white fur; B allele phenotype = black fur  Females that are all heterozygous for X-linked traits are genetic mosaics  Examples of mosaics in humans for X-linked genes o Red-green colorblindness o Anhidrotic ectodermal dysplasia o Any X-linked gene could show this mosaicism Mechanism of X chromosome Inactivation  The mechanism depends on a control region, the “X Inactivation center” or Xic  Xic is sufficient and necessary for X-inactivation  Ectopic localization of Xic in an autosome results in silencing of this autosome  Xic determines all steps in the silencing process including X chromosome “counting”, selection and silencing  Xic encodes several lncRNAs responsible for X-inactivation including the “X-inactive-specific transcript” or Xist  Initiation – in each cell of the embryo, the number of Xics are “counted”  One X-chromosome, either the paternal or the maternal is targeted for inactivation  Xist RNA associates with one X-chromosome starting at Xic locus, recruiting proteins for chromosome compaction 1 BIO 2C03 2013  The same X-chromosome is inactivated in daughter cells  Xic Structure  Xic pairing and counting  Xist expression and X-chromosome inactivation  Figure – in situ hybridization for Xist RNA X Chromosome Counting 2 BIO 2C03 2013 Molecular Basis – Xist Locus  Xist RNA is expressed on the X chromosome selected for inactivation, coating the chromosome  Xist RNA initiates silencing by recruiting chromatin modifying and chromatin remodeling complexes  Xist is a lncRNAs circa 20,000n long Xist lncRNAs recruits the PcG Repressor Complex 2 – PRC2  The Xist lncRNAs recruits PRC2 onto specific binding or “loading” sites where PRC2 interacts with the YY! Repressor  Silencing spreads from the loading sites to the rest of the X chromosome  The Xist lncRNAs is then quickly degraded, limiting silencing to one X chromosome X-Inactivation is controlled by multiple lncRNAs; Xist vs. Tsix lncRNAs  Before X inactivation, Xist expression and activity is antagonized by the synthesis of a lncRNAs designated Tsix  Tsix is an anti-sense transcript interfering with the expression and function of Xist by o Recruiting the DNA methyl transferase Dnmt3a which silences Xist expression o By binding to PRC2, acting as a decoy and titrating PRC2 away from Xist Pluripotency Factors control the expression of Tsix before X inactivation Lecture 2 – Genomic Imprinting (March 28) Genomic Imprinting  Genomic imprinting – the expression of genes is determined by whether the gene is inherited from
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