Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia.
Lorna A FarrellyShuangping ZhengNadine SchrodeAaron TopolNatarajan V BhanuRyan M BastleAarthi RamakrishnanJennifer C ChanBulent CetinErin FlahertyLi ShenKelly GleasonCarol A TammingaBenjamin A GarciaHaitao LiKristen J BrennandIan MazePublished in: Nature communications (2022)
Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we apply an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observe hyperacetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrate that the bromodomain and extraterminal (BET) protein, BRD4, is a bona fide 'reader' of H2A.Z acetylation, and further provide evidence that BET family protein inhibition ameliorates transcriptional abnormalities in patient-derived neurons. Thus, treatments aimed at alleviating BET protein interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.
Keyphrases
- dna methylation
- spinal cord
- endothelial cells
- stem cells
- gene expression
- bipolar disorder
- genome wide
- protein protein
- transcription factor
- induced pluripotent stem cells
- mental health
- binding protein
- pluripotent stem cells
- mass spectrometry
- spinal cord injury
- mouse model
- single cell
- histone deacetylase
- oxidative stress
- bone marrow
- congenital heart disease
- replacement therapy