Biology subjects

Lipska, B. K.

Publications and source records attributed to Lipska, B. K..

2 recordsLinked to original sources

bioRxiv2021

Acetylated Chromatin Domains Link Chromosomal Organization to Cell- and Circuit-level Dysfunction in Schizophrenia and Bipolar Disorder

To explore modular organization of chromosomes in schizophrenia (SCZ) and bipolar disorder (BD), we applied population-scale correlational structuring of 739 histone H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from the prefrontal cortex (PFC) of 568 cases and controls. Neuronal histone acetylomes and methylomes assembled as thousands of cis-regulatory domains (CRDs), revealing fine-grained, kilo-to megabase scale chromatin organization at higher resolution but firmly integrated into Hi-C chromosomal conformations. Large clusters of domains that were hyperacetylated in disease shared spatial positioning within the nucleus, predominantly regulating PFC projection neuron function and excitatory neurotransmission. Hypoacetylated domains were linked to inhibitory interneuron- and myelination-relevant genes. Chromosomal modular architecture is affected in SCZ and BD, with hyperacetylated domains showing unexpectedly strong convergences defined by cell type, nuclear topography, genetic risk, and active chromatin state across a wide developmental window.

genomics↗

bioRxiv2019

Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals disorder-specific expression changes in major psychiatric disorders

How do differences in onset, symptoms, and treatment response arise between various mental illnesses despite substantial overlap of genetic risk factors? To address this question, we carried out deep RNA sequencing of human postmortem subgenual anterior cingulate cortex, a key component of limbic circuits linked to mental illness. Samples were obtained from 200 individuals diagnosed with bipolar disorder, schizophrenia, or major depression, and controls. Differential expression analysis in cases versus controls detected modest differences that were similar across disorders, although transcript-level differences were more pronounced. Case-case comparisons revealed greater expression differences between disorders, including many genes and transcripts that were expressed in opposite directions in each diagnostic group, compared to controls. Relative transcript abundances were associated with common genetic variants that accounted for disproportionate fractions of diagnosis-specific heritability. Inherited genetic risk factors shape the brain transcriptome and contribute to diagnostic differences between broad classes of mental illness.

genomics↗