RESEARCH
Centromeres form the foundation for the chromosomes to attach to a microtubule-based segregation machinery and direct faithful chromosome segregation. Failure to inherit centromeres in perpetuity severely impacts accurate chromosome segregation or genetic inheritance, and reproduction. Surprisingly, centromeres are epigenetically specified by the histone H3 variant, CENP-A. We study how this epigenetic mark, CENP-A, survives challenges during gamete formation and embryogenesis to ensure faithful transmission of genetic information from parent to progeny. We are also interested in how centromere genetics impacts biological funciton and aneuploidy in embryos. We use diverse model systems such as mouse, fly and horse to answer these basic questions.
The two-body problem: Resolving embryo maternal-paternal centromere asymmetry.
Due to vastly different gametogenesis programs the two parental genomes are separated, (“two-bodies”) after fertilization and have considerable epigenetic asymmetry. Consistent with this, the mom and dad genomes have dramatically different centromere strengths.
How are parental centromeric epigenetic differences resolved in embryos to maintain epigenome integrity?
What special features of the embryo epigenome permits erasure of centromeric differences?
We will use both mouse and fly embryos to address these questions.
THE Clock is ticking: Dynamic epigenome stability during reproductive aging.
Mammalian eggs (oocytes) are held in a state of prolonged arrest that can last decades in humans and years in mice until they are recruited for ovulation. A decline in ovarian reserve is thought to be the “biological clock” that triggers female reproductive aging. Age related protein decline is associated with increased oocyte chromosome segregation errors leading to miscarriages, early pregnancy loss and developmental defects.
However, we found that the epigenetic mark at centromeres, in the form of CENP-A nucleosomes, is remarkably resistant to age related decline. This extreme stability contrasts with most other proteins that show marked decay with age.
Das and Destouni, 2022
How does the centromeric histone, essential for chromosome segregation, escape aging to promote its extreme longevity?
What triggers female reproductive aging?
We will tackle this by examining structure-function relationships of the centromere histone, CENP-A during aging. We will also use convergent mammalian models that selectively age ovaries in otherwise young females, to test if this histone is immune to aging triggers.
Stuck on repeat: Centromere Genomics project
We are using fly and horse genome projects to leverage the vast variation in centromere genetics to address any genetic bias to aneuploidy in early embryo. This computational work is in collaboration with the Clarke (fly) and De Mestre (horse) groups.
