Bromodomain and PHD finger containing protein 1 (BRPF1) is a multivalent chromatin reader that acts as a scaffold for histone acetyltransferases KAT6A and KAT6B. The BRPF1 complex plays essential roles in neurodevelopment, with BRPF1 loss leading to neurodevelopmental disorders (NDDs). Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP) is caused by BRPF1 haploinsufficiency. Another BRPF1-associated NDD is 3p25.3 microdeletion syndrome, caused by a variable deletion in the 3p25.3 region that often encompasses BRPF1. Both disorders are characterised by intellectual disability and global developmental delay. Given that acetylation is a reversible process, patients with NDDs associated with acetylation defects may potentially be treated postnatally by supplementing with compounds to promote acetylation, such as acetyl donors or histone deacetylases (HDAC) inhibitors.
The morphological consequences of BRPF1 loss have been extensively modelled in mice, but BRPF1’s molecular mechanism has not been thoroughly investigated owing to issues in reliable detection and low endogenous expression. Thus far, we have successfully endogenously tagged and detected BRPF1 with the HiBiT epitope through CRISPR-Cas9 editing via ribonucleoprotein nucleofection in the neuroblastoma cell line SH-SY5Y. We are further using CRISPR-Cas9 editing in HiBiT-BRPF1 SH-SY5Y cells to introduce a number of IDDDFP patient pathogenic variants. These lines will allow us to study the molecular consequences of IDDDFP-associated variants using protein detection methods such as immunofluorescence microscopy and Western blotting. Furthermore, we will investigate the molecular mechanism of BRPF1 in HiBiT-BRPF1 cells using techniques such as Cut&Run to identify where BRPF1 binds in the genome. The aims of this project are to establish and characterise a model of the disorder states of IDDDFP and 3p25.3 microdeletion syndrome in human cells and mouse models, and test different interventions to treat BRPF1-associated syndromes.