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Females, XX chomosomes and their haplotype

Discussion in 'Ask Jack' started by JanSz, Sep 30, 2021.

  1. JanSz

    JanSz Gold

    How does the above influences females when they attempt to make use of the information on their haplotype?

  2. Jack Kruse

    Jack Kruse Administrator

    Depends how efficient X inactivation is in ladies = a story of transgenerational epigenetics.
    John Schumacher and JanSz like this.
  3. Recent Advances in Understanding the Reversal of Gene Silencing During X Chromosome Reactivation
    • In humans, both X as in female and the sole X chromosome in male cells are coated with an XIST RNA cloud in human ICM cells.
    • Human trophoblast cells reported that the paternal X chromosome is preferentially inactivated.
    • Both X chromosomes are active in the human ICM.
    • Erosion of XCI is characterized by loss of transcriptional silencing, loss of H3K27me3 enrichment, loss of DNA methylation and XACT reactivation.
    • Epigenetic reprogramming of PGCs - scRNA-seq was used to investigate XCR in human PGCs and XCR was found to occur as early as week 4 onwards during human embryo development.
    Conversion of random X-inactivation to imprinted X-inactivation by maternal PRC2 –
    • Looking into the role of core zygotic Polycomb repressive complex 2 (PRC2) protein in the initiation of imprinted X-inactivation.
    • At the onset of imprinted X-inactivation, Xist expression dynamics in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived maternal PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals.
    One question is: can the transcribed genes be reimprinted? –

    What we believe we understand:
    Heterochromatin components
    Pericentric heterochromatin contains a large number of proteins, but its most distinctive feature is the presence of megabasesized repetitive DNA domains coated in a specifc histone H3K9 trimethylation mark, which is deposited by the enzymes SUV39 and SETDB1. This mark is bound by the chromo domain of SUV39H1, which stimulates catalytic activity of the enzyme. Furthermore, the same mark is bound by the HP1 protein, which can bridge adjacent nucleosomes. Therefore, heterochromatin components can both write and read the H3K9me3 mark and compact their target chromatin. Heterochromatin factors also collaborate with RNAi in plants, yeast and some animals to convey epigenetic inheritance.
    Polycomb proteins
    Early genetic studies classifed Polycomb (PcG) and Trithorax into two antagonistic groups that maintain the memory of spatial patterns of expression of homeotic genes throughout development. These complexes also have key roles in the maintenance of developmentally or environmentally programmed expression states, such as X-chromosome inactivation or cold-induced vernalization in plants. PcG proteins are found in two main classes of complex— PRC2 and PRC1—that are responsible for deposition of the H3K27me3 and H2AK119Ub marks via EZH2 and RING1A/1B, respectively. PcG proteins can be recruited to specifc regions of the genome by DNA-binding proteins or noncoding RNAs3. PRC2 complexes contain a writer, the histone methyltransferase enzyme EZH2 (or its less efcient paralogue EZH1), and a reader, the EED subunit. Similar to HP1, CBX subunits of PRC1 complexes contain a chromodomain that specifcally recognizes H3K27me3. Finally, another PRC1 subunit, PHC1-3, can oligomerize and induce 3D clustering in nuclear foci in vivo3.
    Noncoding RNAs
    Noncoding RNAs (ncRNAs) belong to several classes, and neither their production nor their functions can be generalized. Many ncRNAs, such as microRNAs, regulate post-transcriptional processes, whereas others are involved in transcriptional regulation. Short noncoding RNAs, such as short interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs), are shorter than 30 nucleotides, whereas long noncoding RNAs (lncRNAs) vary in size (up to more than 100 kilobases). The best characterized of these is probably the X-inactive specifc transcript (Xist). Many short ncRNAs act within or outside chromatin, and some, for example siRNAs and tRNA fragments, can difuse extracellularly, whereas many nuclear lncRNAs are chromatin-associated. Enhancer RNAs can activate genes, but most short and long ncRNAs are repressive, act via chromatin (H3K9me3, Polycomb) or DNA methylation1, and can induce epigenetic memory by building self-enforcing loops with heterochromatin or the RNAi machinery. They are also involved in the regulation of higher-order chromatin architecture.
    DNA methylation
    The mechanisms that allow DNA methylation to be copied during DNA replication represent one of the best-understood epigenetic systems, and involve specifc proteins that recognize CpG hemimethylated DNA and thereby redeposit DNA methylation on newly replicated DNA. DNA methylation is maintained by the DNA methyltransferase DNMT1 and its partner UHRF1 (also known as NP95), which specifcally binds hemimethylated DNA and stimulates DNMT1 via its ubiquitin ligase activity. Therefore, as recently reviewed in detail, a single complex contains both the ‘writer’ and the ‘reader’ of the epigenetic methyl CpG mark, and both moieties are essential for the maintenance of DNA methylation.

    https://hal.archives-ouvertes.fr/hal-02367550/document Major carriers of epigenetic information

    However, connecting the dots of X-inactivation, PRCS, XCI, haplotype with epigenetics...

    We know we can snip genetic code using a virus or a bacteria. We can then insert a fragment of code in between the cut genetic code and hope for the best.
    CRISPR gene editing in human embryos - https://www.nature.com/articles/d41586-020-01906-4
    mRNA gene therapy - https://www.nature.com/articles/s41435-021-00136-6
    mRNA vaccine called (BNT162b2)​

    We also know Nature can gene edit using the environment over time.
    Last edited: Oct 6, 2021
    JanSz likes this.

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