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, reproduction, and ultimately species continuity. Surprisingly, centromeres are epigenetically specified by the histone H3 variant, CENP-A, and centromere identity strictly depends on the presence and persistence of CENP-A nucleosomes. 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 use diverse model systems such as mouse, fly and horse to obtain a holistic understanding of this fundamental problem in chromosome biology: how an epigenetic mark is inherited parallel to DNA. We focus on two specific challenges of epigenetic centromere inheritance in the germline outlined below.
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. This presents a challenge to embryos as maternal-paternal centromere asymmetry causes genome instability. We will explore how embryos overcome this fundamental problem by addressing the following:
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 and degradation of proteins within oocytes. 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?
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. Ultimately, identifying the age resistant mechanism of the core centromeric nucleosome will reveal the elusive links between ovarian aging signals and the internal chromatin associated proteostasis.