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

by Rahman, Samir , Kundakovic, Marija , Phillips-Cremins, Jennifer E , Lewis, David A. , Zharovsky, Elizabeth , Brown, Leanne , Jacobov, Rivky , Tamminga, Carol A. , Marenco, Stefano , Dracheva, Stella , Devillers, Olivia , Akbarian, Schahram , Girdhar, Kiran , Bendl, Jaroslav , Kozlenkov, Alexey , Johnson, Jessica S. , Flatow, Elie , Haroutunian, Vahram , Jiang, Yan , Couto, Lizette , Gilgenast, Thomas , Lipska, Barbara K. , Fullard, John F. , Hoffman, Gabriel E. , Park, Royce , Roussos, Panos , Kassim, Bibi S. , Peters, Mette A. , Gur, Raquel E. , Liao, Will , Hahn, Chang-Gyu , Dong, Pengfei , Wiseman, Jennifer R

in Genomics

2021

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

in Genomics

2021

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

in Genomics

2021

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Paper

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

Rahman, Samir,

Kundakovic, Marija,

Phillips-Cremins, Jennifer E,

Lewis, David A.,

Zharovsky, Elizabeth,

Brown, Leanne,

Jacobov, Rivky,

Tamminga, Carol A.,

Marenco, Stefano,

Dracheva, Stella,

Devillers, Olivia,

Akbarian, Schahram,

Girdhar, Kiran,

Bendl, Jaroslav,

Kozlenkov, Alexey,

Johnson, Jessica S.,

Flatow, Elie,

Haroutunian, Vahram,

Jiang, Yan,

Couto, Lizette,

Gilgenast, Thomas,

Lipska, Barbara K.,

Fullard, John F.,

Hoffman, Gabriel E.,

Park, Royce,

Roussos, Panos,

Kassim, Bibi S.,

Peters, Mette A.,

Gur, Raquel E.,

Liao, Will,

Hahn, Chang-Gyu,

Dong, Pengfei,

Wiseman, Jennifer R

2021

Overview

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.

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Publisher

Cold Spring Harbor Laboratory

Subject

Genomics