# The 3D genome in transcriptional regulation across the postnatal life span, with implications for schizophrenia and bipolar disorder

> **NIH NIH U01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $1,173,570

## Abstract

PROJECT SUMMARY
Genome wide association studies of complex neuropsychiatric diseases, including schizophrenia (SCZ) and
bipolar disorder (BD), have identified numerous risk loci that are mostly situated in non-coding regions,
necessitating a systematic study of non-coding regulatory elements. It has also been established that SCZ risk
loci are preferentially located within promoter and enhancer regulatory sequences of neurons and that they co-
localize with expression Quantitative Traits Loci (eQTL), thus implicating specific genes. However, work that
has been performed to-date has limited spatiotemporal resolution as: (1) only a few cortical regions have been
examined, (2) the effect of 3D genome on transcriptional regulation across the lifespan has never been
examined, and (3) studies have been limited to homogenate brain tissue or include only broadly defined
neuronal and non-neuronal populations. To address these limitations, we will generate cell type-, brain region-
and age period-specific high-dimensional data that will inform us of the effect of 3D genome on the
transcriptional regulation and will link regulatory elements with specific transcripts. In Aim 1, we will examine
the impact of SCZ and BD risk variants on 3D genome structure and transcriptional regulation. We will use
fluorescence activated nuclei sorting to isolate glutamatergic and GABAergic neuronal as well as
oligodendrocyte and astrocyte nuclei from five human cortical and subcortical regions relevant to SCZ and BD
across five postnatal age periods. We will then generate cell-type specific annotations for gene expression and
enhancer RNA (RNA-seq and CAGE-seq), open chromatin (ATAC-seq), insulators (CTCF ChIP-seq), active
enhancers and promoters (H3K27ac and H3K4me3 ChIP-seq), and chromatin loop interactions (HiC and
Capture-C). Using the resulting data, we will delineate cis transcriptional regulation associated with the 3D
genome (including promoter-enhancer loopings) and uncover the functional consequences of SCZ and BD risk
loci on enhancer-transcript units. In Aim 2, we will examine the impact of SCZ and BD risk variants on cell
type-specific gene expression and epigenome QTLs. We will map RNAseq and ATACseq at the single cell
level and will use cell type-specific markers and deconvolution approaches to the existing large scale
transcriptome and epigenome datasets, from CommonMind consortium, psychENCODE and other projects, in
order to generate cell type-specific expression and epigenome QTLs. We will then co-localize SCZ and BD risk
loci with expression and fine map epigenome QTLs to define disease-associated enhancer-transcript units.
Finally, in Aim 3, we will validate disease-associated enhancer-transcript units by epigenomic editing of risk loci
in iPCS-derived cells. We will apply the CRISPR/Cas9 to activate (p300) or inhibit (KRAB) enhancers of the
disease-associated enhancer-transcript units (Aims1-2). Lastly, we will introduce epigenomic perturbations and
char...

## Key facts

- **NIH application ID:** 9977708
- **Project number:** 5U01MH116442-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Schahram Akbarian
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,173,570
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977708

## Citation

> US National Institutes of Health, RePORTER application 9977708, The 3D genome in transcriptional regulation across the postnatal life span, with implications for schizophrenia and bipolar disorder (5U01MH116442-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977708. Licensed CC0.

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