Unpicking functional redundancy between BAF complex bromodomains during trophoblast maintenance and differentiation

The placenta is a complex organ essential for foetal growth and survival within the uterus. Defects in placenta formation and function can have profound and lifelong consequences to both mother and child. The foetal component of the placenta consists largely of highly specialized cells known as "trophoblasts", of which there are multiple subtypes of distinct morphology and function. For example, some trophoblasts control maternal-foetal waste and nutrient exchange while others remodel the maternal vasculature to enhance blood supply to the developing foetus. The identity and function of different cell types is determined by the combination of genes which are active in the cells. This is partly determined by which genes are available to the gene transcription machinery. Gene accessibility is controlled by proteins known as chromatin remodellers. The BAF chromatin remodelling complex finds the correct location in the genome by binding chemical modifications on DNA packaging proteins called histones, to then make genes accessible. The BAF complex binds these chemical modifications using bromodomains (BRDs). However, the BAF complex has multiple different BRDs that bind different chemical modifications. Whether the different BRDs have redundant or independent functions is unknown. We will use a combination of drugs and CRISPR genome editing to prevent functions of different BRDs, and determine whether this influences which genes are activated and thus the formation of different trophoblast cell types. The outcome will be essential progress towards understanding how the diverse set of chemical modifications on histones, known as the "histone code" is interpreted to control the formation of complex tissues and organs. It will also provide key insights into how the placenta develops and how errors can lead to pregnancy complications.