Transcriptional repression of Xi

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1 Transcriptional repression of Xi Xist Transcription of Xist Xist RNA Spreading of Xist Recruitment of repression factors. Stable repression Translocated Xic cannot efficiently silence autosome regions. A XX ES cell line with T(X;4)37H translocation 12

2 The spread of mh3k27 into chromosome 4 region is inefficient. H3K27me3 is largely confined to the X chromosome. TMA: differentiated ES cells T37H: adult fibroblasts Histone acetylation (ach4) mark is maintained on chromosome 4. 13

3 Xist RNA is largely limited to X chromosome. Mapping of the translocation breakpoint X-chromosome is enriched for LINE (long interspersed element) Translocation breakpoint The block to Xist spreading coincides with a region high in gene content but low in LINE. 14

4 Cytosoine methylation contributes to the maintenance of X inactivation. CCGCGG CCGG c/c: Dnmt1 -/- Emb: embryo YS: yolk sac Exon 1 of Xist Xa Xi Xa Y Xist Gene subject to X-inactivation Cytosine methylation In the absence of cytosine methylation, X inactivation in the embryo is initiated, but not stably maintained. WT E8.5 lacz Dnmt c/c E8.5 X-inactivation is initiated normally in embryo. lacz Dnmt c/c E9.5 X-inactivation is not maintained. lacz lacz LacZ is on the paternal allele. 15

5 Imprinted X inactivation in extraembryonic tissue does not require cytosine methylation. Imprinted X-inactivation in extraembryonic tissue Msg1 promoter lacz Maternal Paternal ve: visceral endoderm, part of extraembryonic tissue SmcHD1 is critical for X-inactivation. Structural maintenance of chromosome hinge domain Identified as a modifier of transgene silencing Homozygous mutation of SmcHD1 leads to lethality in females. MommeD1: ENU-induced mouse mutant SmcHD1 gene trap (gt): inactivation of SmcHD1 by marker integration 16

6 X-inactivation is impaired in SmcHD1 -/- mutant. E7.5 Embryo Placenta SmcHD1 + Xist + GFP + Xist - SmcHD1 - Xist + GFP + Xist - P M P M E10.5 Xist activation and H3K27me3 localization appear normal in SmcHD1 Homozygous mutant. 17

7 SmcHD1 localizes to the inactive X chromosome. Reactivation of genes on Xi is accompanied by DNA demethylation. 18

8 H3K27me3 is dispensable for random X inactivation, but is required for the maintenance of imprinted X inactivation. Xist Tsix GFP Tsix mutation leads to strong expression of Xist and preferential X-inactivation of GFP marked chromosome. Eed is part of the complex that catalyzes H3K27me3. H3K27me3 is undetectable in Eed -/- embryos. At E5.5, extraembryonic tissues have undergone imprinted X-inactivation (paternal X with GFP), while both X chromosomes remain active in embryo. The imprinted X-inactivation is erased in the embryonic epiblast cells at this stage. Imprinted X-inactivation is initiated normally in the absence of Eed, but X-inactivation is not stably maintained in some trophoblast cells (TB). Random X inactivation is normally initiated and maintained in the embryo in the absence of Eed; but imprinted X-inactivation is not maintained. 19

9 Monoallelic expression of X-linked genes in Eed embryos. Some genes (15%) escape X-inactivation in human. Pseudo autosome genes Significant expression from Xi Silenced on Xi Expression measured from 9 lines of human/rodent hybrid cells containing Xi. Each line represents data from one hybrid cell line. 20

10 References X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency: heterozygote has two clonal populations. Science 160, 425 (1968). A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38 (1991). Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351, 329 (1991). The product of the mouse Xist gene is a 15kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515 (1992). Requirement for Xist in X chromosome inactivation. Nature 379, 131 (1996). Xist RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. The Journal of Cell Biology 132, 259 (1996). Tsix, a gene antisense to Xist at the X-inactivation centre. Nature Genetics 21, 400 (1999). Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99, 47 (1999). X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Developmental Biology 225, 294 (2000). Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 107, 727 (2001). Role of histone H3 lysine 27 methylation in X inactivation. Science 300, 131 (2003). X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400 (2005). The Polycomb group protein EED is dispensable for the initiation of random X- chromosome inactivation. PloS genetics 2, e66 (2006). Attenuated spread of X-inactivation in an X;autosome translocation. PNAS 103, 7706 (2006). X chromosome reactivation initiates in nascent primordial germ cells in mice. PloS genetics 3, e116 (2007).

11 SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nature Genetics 40, 663 (2008). RNF12 is an X-encoded dose-dependent activator of X chromosome inactivation. Cell 139, 999 (2009). Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. Nature 467, 977 (2010). RNF-12 activates Xist and is essential for X chromosome inactivation. PloS genetics 7, e (2011). Regulation of X-chromosome inactivation by the X-inactivation centre. Nature Reviews Genetics 12, 429 (2011). Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nature Reviews Genetics 12, 542 (2011).

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