2. flies
increase the amount of transcripts from
the single X in males to equal the output of
the two X chromosomes in females
Types of
dosage worms
reduce the level of transcription of each of
the two X chromosomes in females
so that they jointly equal that of the single
male X
compensation
mammals
silence all but one X in
cells of both sexes
5. Why are the X-chromosome & XCI important?
• ~1000 genes on the X-chromosome
• X = responsible for sexual dimorphism (along with Y)
• Enriched for genes responsible for reproduction & brain development,
behavior, and cognition
• >200 disease genes on the human X chromosomeMany genes responsible for
neurodevelopmental disorders, autism, and other intellectual disabilities
Rett Syndrome (mostly female)
Fragile X Syndrome (male & female)
Duchenne muscular dystrophy (mostly male)
6.
7.
8.
9. Functional elements within the X-inactivation centre
The XIC contains four non-translated RNA genes, Xist, Tsix, Jpx and Ftx, which are involved in
X-inactivation. The XIC also contains binding sites for both known and unknown regulatory
proteins
10. The X-Inactivation Center (Xic) is populated
by long noncoding RNA
• 100-200 kb region
• Xic necessary & sufficient to drive silencing on any chromosome
• 1990s- Sequencing of Xic reveals few, if any, protein-coding genes
• Xic enriched for long noncoding RNA
11.
12.
13.
14. Model: Functional Antagonism
Jpx and CTCF titrate each other (X:A)
• CTCF represses Xist promoter
• Jpx RNA activates Xist promoter
Do the two factors interact functionally?
Part of the X:A titration mechanism?
15. Xist
• 17-20 kb long noncoding RNA
• Transcribed only from Xi
• Required to initiate X-inactivation
• "Coats" the Xi
• Xist RNA binds only "in cis“
• Spreading requires only the Xic, not
other X-specific elements
16. Model for symmetry breaking:
Xite and Tsix RNAs target CTCF to the pairing center
17.
18.
19.
20. It is understood that X-chromosome inactivation is a random process, occurring at about the time
of gastrulation in the epiblast (cells that will give rise to the embryo). The maternal and paternal X
chromosomes have an equal probability of inactivation.
Inactivation occurs on a cellular level, resulting in a mosaic expression, in
which patches of cells have an inactive maternal X-chromosome, while other
patches have an inactive paternal X-chromosome
21.
22. Why we need to study this?
The goal of chromosome therapy is to ameliorate the effects of an abnormal
chromosome in the cells.
23. Chromatin remodeling on the inactive X chromosome
Over the past decade, a growing number of histone
modifications have been associated with the inactive
X chromosome, and many of these are generally
associated with silent chromatin in the genome
24. Another important point is that not only an abnormal number of chromosomes cause
disease: a failure of the XCI mechanisms can also cause it:hypomethylation of the X-chromosome, or mutations in
the XCI escape system, also cause disease. For example, reactivation of the silenced X-chromosome has been
documented in breast or renal cancer This hypothesis was also reported for other cancers,but studies in the area
are not sufficient
The maintenance of gene silencing in X-inactivation is a complex phenomenon that involves the interaction of many
different cellular mechanisms and pathways. Further, recent studies showed that XCI is not as stable as previously
thought. Reactivation of some Xi genes was observed in normal and diseases tissues, e.g., upon ageing, in autoimmune
diseases and cancer . The normal progression of this process is not the same in every cell lineage: it has been reported
that immune cells, e.g., have a diverse process of XCI maintenance, what actually has been reported as a possible cause
of the well-known imbalance in autoimmune diseases between men and women .
