# Epigenomic Regulation of a Large, Neuron-specific Chromatin Domain

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $411,829

## Abstract

The genome of brain cells is organized into thousands of `topologically associated domains' (TADs), with the
linear genome folded upon itself across hundreds of kilobases. A deeper understanding of TAD regulation
and function will advance knowledge about epigenomic and genetic risk architectures of neuropsychiatric
disease. However, to date regulatory mechanisms governing TAD structure and function in brain cells
remain completely unexplored. In this proposal, we will study neuronal maintenance of a subset of very
large, mega-base scale `superTADs' that critically depend on Set-domain-bifurcated 1 (Setdb1/Eset/Kmt1e),
encoding a histone H3-lysine 9 methyltransferase. This includes the 1.2 megabase-spanning topologically
associated domain at the clustered Protocadherin (cPcdh) locus, encompassing >70 Pcdh and non-Pcdh
genes important for neuronal connectivity.
We propose to dissect, in vivo, the regulatory layers governing the neuronal 3D genome, including SETDB1-
sensitive neuronal superTADs. Aim #1 will test the hypothesis that SETDB1 shields neuronal genomes
from excess binding by the multifunctional chromatin organizer CCCTC binding factor (CTCF). To this end,
we will map, by in situ Hi-C assays, the 3D genomes of glutamatergic projection neurons in adult cerebral
cortex and inhibitory projection neurons of cerebellar cortex, comparing wildtype with Setdb1 and Ctcf
deficient neurons. Aim #2 will explore single cell-stochastic constraint of cPcdh genes, including potential
alterations after Setdb1 and Ctcf ablation and after (epi)genomic editing of loop-bound non-coding
sequences within the local superTAD. Furthermore, we will study of functional connectivity after neuron-
specific deletion of Setdb1 and Ctcf. We will assess changes in synaptic drive onto top-down rostromedial
frontal-to-visual cortex projection neurons between adolescence and adulthood, with projection-specific
whole-cell patch clamp recordings of miniature excitatory (mEPSC) postsynaptic currents at multiple
developmental time points, together with dendritic spine characterization. Taken together, the experiments
proposed here will provide deep insights into regulatory mechanisms governing the maintenance and
function of large megabase-scale higher order chromatin structures in mature neurons. This includes an
intriguing role of the chromosomal connectome inside neuronal nuclei shaping the brain's connectome, by
regulating expression of the cPcdh genes.

## Key facts

- **NIH application ID:** 9934013
- **Project number:** 5R01MH117790-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Schahram Akbarian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,829
- **Award type:** 5
- **Project period:** 2018-07-09 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934013

## Citation

> US National Institutes of Health, RePORTER application 9934013, Epigenomic Regulation of a Large, Neuron-specific Chromatin Domain (5R01MH117790-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934013. Licensed CC0.

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