Why, When and How of X Chromosome Inactivation?
Quoting Theodosius Dobzhansky, “Nothing in biology makes sense except in the light of evolution”, the need for imposing dosage parity arose with the evolution and divergence of sex chromosomes as gene-rich X and gene-poor Y. Both deficiency as well as an excess of chromosome(s) or gene products can threaten the survival of an organism is best explained by the fact that the aneuploidies or polyploidies of certain large gene-rich chromosomes leads to abnormal conditions such as cancer. Therefore, it is of utmost significance for an organism to design a mechanism to counteract the dosage imbalance problem, which in mammals is taken care of by transcriptional silencing of one of the X chromosomes in females, referred to as X chromosome inactivation (XCI)
The process of XCI has been a paradigm to understand the epigenetic regulation on a chromosome wide scale since its discovery by Mary Lyon in 1961. Briefly, both the X chromosomes are active in the early zygote and the process is initiated during the implantation stage, coinciding with the differentiation of pluripotent stem cells into various cell types. The choice of X chromosome to be inactivated is random i.e., both maternal X (Xm) as well as paternal X (Xp) have an equal probability of undergoing inactivation. This generates a mosaic of somatic cells with either Xm or Xp active, as exemplified by the variegated coat colour pattern in tortoiseshell cats.
At the molecular level, initiation of XCI is marked by the upregulation of an X-linked long non-coding RNA – Xist from one of the X chromosomes, which physically coats the entire X chromosome in cis. This is followed by the exclusion of RNA Polymerase II, removal of active histone marks, enrichment of repressive histone modifications and DNA methylation of promoters of X-linked genes causing heterochromatinization of the majority of X chromosome rendering it transcriptionally inactive. Once silenced, Xi is stably maintained in a mitotically heritable manner.
We are interested in understanding the structural as well as transcriptional regulatory roles of chromatin organization in influencing the establishment of XCI by attempting to address the following broad questions:
What factors govern the chromatin architecture of X undergoing inactivation?
Do these factors influence the kinetics of XCI?