Developmental epigenetic regulation through the lens of X-chromosome inactivation and reactivation.
Emerging evidence implicates that epigenetics plays a major role in developmental processes. However, often dysregulation of epigenetic processes leads to different human diseases such as cancer. Unlike irreversible mutations in DNA, epigenetic modifications are reversible. This inherent plasticity makes epigenetic changes associated with human diseases potentially amenable to manipulation via therapeutic intervention. Therefore, understanding of epigenetic regulation is crucial for our comprehension of the alterations that can lead to disease. However, much about the mechanistic aspects of epigenetic regulation remains to be understood. Our research strives to further the understanding of mechanism of epigenetic regulation through the study of X-chromosome inactivation and reactivation during transition of pluripotent sub states using mouse embryo and stem cells.
During development, pluripotency first arises in the inner cell mass of pre-implantation blastocyst in a naïve state and progresses to a primed state in the post-implantation epiblast that is then lost upon lineage commitment. These transient pluripotent states in vivo are recapitulated in vitro. Mouse embryonic stem cells (ESC) represent the naïve state, whereas mouse epiblast stem cells (EpiSC) represent the primed state. One hallmark epigenetic change during transition from naïve to primed pluripotent state in female cells is X-chromosome inactivation. During X-inactivation, one of the two X-chromosomes in female mammals is transcriptionally inactivated in order to equalize X-linked gene expression between the sexes. Once inactivated, replicated copies of the inactive and the active-X maintain their respective transcriptional states through future rounds of cell division. X-inactivation is essential for the viability and proper development of female mammals and serves as a paradigm of epigenetic transcriptional regulation. Notably, reprogramming of primed pluripotent state to naïve state leads to the reactivation of the inactive-X. Much about the mechanistic aspects and connection of X-inactivation and reactivation with transition of different pluripotent states remains elusive. Therefore, overall goal of our group is to define the underlying relationship and mechanisms of X-inactivation and reactivation with the transition of pluripotent states. The long-term goal of these studies is not only to advance our understanding of basic epigenetic mechanisms during development, but also to provide critical insights into developing new therapeutic approaches to treat human diseases.
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