Marnie Blewitt-Projects

Marnie Blewitt-Projects

Projects

Screening for novel epigenetic modifiers using X inactivation as a model system

A major stumbling block to understanding epigenetic control is that we do not know the identity of all of the factors involved in epigenetic control, and therefore our understanding of the molecular mechanisms of epigenetic control will necessarily be incomplete. We are performing in vitro screens using our bespoke shRNA library against ~1100 known or potential epigenetic modifiers to identify new roles for known players plus uncharacterised epigenetic modifiers. Our primary screen utilises novel ES cells to rapidly analyse X inactivation, as a model epigenetic system. Positive hits are characterised for their role in X inactivation, and more broadly studied in pluripotency, development and disease.

Team members: Andrew Keniry, Natasha Jansz, Andrés Tapia del Fierro, Kelsey Breslin, Joy Liu, Maddy Dawson

Characterizing the molecular function of Smchd1 and screening for small molecules that modulate Smchd1 activity

SMCHD1 was recently found to be mutated in the muscular dystrophy FSHD2, and also contribute to disease severity in related FSHD1.

We are actively studying how Smchd1 functions as an epigenetic repressor, using genomic technologies, biochemical and biophysical assays and structural biology approaches to reveal how it is able to perform its role to switch genes off. We are also studying how SMCHD1 function may be targeted to treat FSHD and other disease.

We have an active small molecule drug discovery program, looking for molecules that directly bind and enhance Smchd1’s enzymatic activity. Furthermore, we are investigating whether such molecules could also be used in other scenarios where Smchd1 plays a role, for example in genomic imprinting.

Team members: Kelan Chen, Natasha Jansz, Sarah Kinkel, Tamara McLennan, Kelsey Breslin