The exploration of brain epigenomes, including DNA methylation and covalent histone modifications, has provided fundamentally new insights into the mechanisms of brain ontogenesis and maturation. Moreover, deleterious mutations and rare structural variants in more than 50 genes encoding various types of chromatin regulators have been linked to neurodevelopmental diseases, including autism spectrum disorders (ASDs). Therefore, it is now generally accepted that proper regulation of chromatin structure and function during pre- and early postnatal development is critically important for the proper unfolding of cognitive abilities and emotional states. ASDs are a group of neurodevelopmental conditions bound together by broad syndromic overlap, with key behavioral deficits in social interaction, communication, and motor behavior including stereotypies. There is a strong genetic contribution to ASDs, yet environmental influences may also be etiologically important. Only a few studies, however, studied chromatin structures in diseased tissue (i.e., postmortem brain tissues from ASD subjects). In addition, epigenetic regulations, including histone modification landscapes, are highly specific for cell type, which is a key challenge for the field given the enormous cellular heterogeneity of the brain tissue, with multiple sub-population of inhibitory and excitatory neurons and various types of non-neuronal cells residing in the same tissue blocks. In this exploratory proposal, we will develop and test radically novel approaches in the human brain research, including the sorting of multiple subtypes of cortical neurons and the cell type-specific charting of 3- dimensional chromosomal architectures at selected genomic loci, with focus on ASDs. Specifically, we will profile open chromatin-associated histone methylation and acetylation, and promoter-enhancer associated chromosomal loop formations in GABAergic interneurons derived from the medial ganglionic eminence (MGE), in comparison to other neurons from ASD and control brains. If successful, the experiments proposed here will push the existing frontiers in human brain research, and for the first time, draw a connection between regulatory non-coding DNA, chromosomal architectures, and histone methylation profiles in multiple neuronal subtypes in health and disease.
This application will explore potential changes in chromatin (here defined as the organization and packaging of the genome inside the cell nucleus) in specific cell types collected from brain of subjects on the autism spectrum, in comparison to controls.
|Ibi, Daisuke; de la Fuente Revenga, Mario; Kezunovic, Nebojsa et al. (2017) Antipsychotic-induced Hdac2 transcription via NF-?B leads to synaptic and cognitive side effects. Nat Neurosci 20:1247-1259|
|Kozlenkov, Alexey; Wang, Minghui; Roussos, Panos et al. (2016) Substantial DNA methylation differences between two major neuronal subtypes in human brain. Nucleic Acids Res 44:2593-612|
|Halene, Tobias B; Kozlenkov, Alexey; Jiang, Yan et al. (2016) NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure. Schizophr Res 170:235-44|
|PsychENCODE Consortium; Akbarian, Schahram; Liu, Chunyu et al. (2015) The PsychENCODE project. Nat Neurosci 18:1707-12|