Haploinsufficiency of select chromatin regulators is frequently associated with autism. Chromatin regulators are broadly expressed in many brain and non-brain cell types, and reduced dosage is frequently associated with syndromic brain disorders. Studies of chromatin biology have revealed that different chromatin structures exhibit distinct sensitivities to epigenetic perturbation. However, why neurons are particularly vulnerable to haploinsufficiency of these factors during development is unknown.
Gordon Fishell and colleagues hypothesize that a brain-specific chromatin structure may be uniquely susceptible to haploinsufficiency of autism-linked chromatin factors. To explore this possibility, Fishell and his team plan to map the chromatin landscape in major subtypes of cortical interneurons, the dysfunction of which has been implicated in autism. Specifically, they plan to perform CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assays1 to identify chromatin marks on parvalbumin-, somatostatin- and vasoactive intestinal peptide-expressing interneurons purified from adult mouse cortex. The resulting high-resolution epigenomic maps will enable Fishell’s lab to examine chromatin organization in these rare neuronal populations. They hope to discover the presence of unique chromatin structures on genes critical for the development of each interneuron subclass. They hypothesize that these structures are bound by key chromatin regulatory factors such as Chd8, mutations of which are associated with autism.
Collectively, Fishell and colleagues’ expectation is that their efforts will allow them to explore how the unique vulnerability of brain development to mutations of ubiquitous chromatin factors linked to autism relates to their cell-type-specific requirement in the brain. Moreover, this work has the potential to identify convergent functions of multiple autism-linked chromatin factors.