# In vivo multiplexed silencing of cis-elements in the brain

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $419,375

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a major personal and public health crisis in the United States and the incidence is
increasing. Metabolic and inflammatory disorders contribute to AD risks by driving gene regulation and
expression changes. Indeed, epigenetic changes during aging could reveal important therapeutic targets for
preventing AD. The long-term goal of our work is to uncover the core cis-elements and gene regulatory networks
(GRNs) that control AD risks. A challenge is that GRNs involve multiple cis-regulatory elements and genes
across the genome. Currently, methods are lacking to functionally study combinations of cis-elements in vivo
using mouse models, which is a barrier blocking us from identifying GRNs that can prevent or resolve AD
pathology. The goal of this collaborative study between the Gregg and Gertz labs at the University of Utah
is to develop an approach in mice to study the functions of combinations of cis-elements in vivo. The
project will create a platform technology for functional studies of GRNs, facilitating the identification of
conserved GRNs that can prevent or resolve AD pathology. The approach can be applied to many
biological problems. In a recent Cell Systems paper, we (Gertz lab) devised a CRISPR- based technique that
enables simultaneous epigenetic deactivation of multiple enhancers. The method is called Enhancer-
interference (Enhancer-I) and can maintain stable silencing of up to 50 loci simultaneously. Enhancer-I was
developed for in vitro studies and an Enhancer-I system for in vivo epigenome editing in mouse models does not
yet exist. Therefore, we are collaborating with the Gregg lab to adapt Enhancer-I for in vivo work. The Gregg lab
has extensive experience studying epigenetics and gene regulation in mice and recently published studies
uncovering an atlas of conserved cis-elements and GRNs that are candidates for controlling processes involved
in AD, including obesity, inflammation and neurodegeneration. Here, we will collaborate to create a mouse
model of the Enhancer-I system for multiplexed in vivo epigenome editing. For proof-of-principle, we target
cis-elements controlling Tau, beta-amyloid precursor protein (App), the Fat Mass & Obesity (FTO) locus and
other important AD risk loci. Enhancer-I will empower researchers to study the functions of combinations of cis-
elements and define functional GRNs controlling AD pathology in vivo. Our technology will help open new areas
of study.

## Key facts

- **NIH application ID:** 10217662
- **Project number:** 1R21AG067350-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jason Gertz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,375
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217662

## Citation

> US National Institutes of Health, RePORTER application 10217662, In vivo multiplexed silencing of cis-elements in the brain (1R21AG067350-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217662. Licensed CC0.

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