# Chromosomal Conformations in Mouse Depression Models

> **NIH NIH P50** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $220,350

## Abstract

PROJECT SUMMARY – PROJECT 2
Project 2 made considerable progress over the past four years in defining the influence of several histone
methyltransferases and demethylases, acting in prefrontal cortex (PFC) neurons, in controlling depression-
related phenomena. A major finding from this work is that genome regulation is often “punctate” as opposed to
continuous and affects certain clusters along the genome. Consistent with this notion is our evidence that
depression-related epigenetic regulation partly bypasses the linear genome and affects the 3D structure of
chromatin. One of the most dramatically affected genomic regions is the Pcdh locus, which expresses
numerous isoforms of protocadherins, strongly implicated in neuronal growth and synapse formation, but
poorly understood in adult brain, let alone depression. Importantly, the Pcdh locus also displays robust
regulation in the Center's genome-wide datasets, including dramatic induction in PFC of mouse models and
depressed humans, effects seen in males and females, and Pcdh genes are among the most highly induced in
PFC by early life stress. We will now further characterize the influence of the 3D genome, with particular
attention to Pcdh, in depression in several key ways. We will study how manipulation of specific proteins which
control 3D chromatin structure in PFC neurons influence depression-related behavioral abnormalities. We will
use gene-editing tools, with the Chromatin and Gene Analysis Core, to modify the Pcdh locus and study
directly its influence in depression models. This is a required approach, since the large number of Pcdh genes
and compensatory changes in other isoforms when a single isoform is manipulated has made it difficult to
characterize protocadherin function in adult brain. We will also map how chronic stress alters the 3D genome
in PFC neurons, both focusing on Pcdh as well as the global genome, with parallel studies of depressed
humans performed in Project 4. Finally, we will employ a novel method to retrospectively map how the 3D
genome is altered by early life stress when examining adult mice based on their susceptibility to subsequent
stress. Together, these studies will reveal how Pcdh genes influence depression-related phenomena and
provide fundamentally new information about the 3D genome in adult neurons.

## Key facts

- **NIH application ID:** 9878921
- **Project number:** 5P50MH096890-09
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Schahram Akbarian
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $220,350
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878921

## Citation

> US National Institutes of Health, RePORTER application 9878921, Chromosomal Conformations in Mouse Depression Models (5P50MH096890-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9878921. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*