# Effects of mRNA m6A methylation and its YTHDF reader proteins on human AD mRNA homeostasis

> **NIH NIH RM1** · UNIVERSITY OF CHICAGO · 2023 · $424,102

## Abstract

ABSTRACT
Effects of mRNA m6A methylation and its YTHDF reader proteins on human AD mRNA homeostasis
Alzheimer’s disease (AD) is the leading cause of dementia in the United States but has no disease-modifying
treatments. Epigenetic regulation has been shown to play pivotal roles in neurodevelopment and
neurodegenerative disorders. In addition to DNA and histone modifications, more than 150 post-transcriptionally
modified ribonucleosides have been identified in various types of RNA. Studies in the past decade suggest that
post-transcriptional mRNA modifications can notably affect gene expression. For example, about 0.4-0.6% of all
adenosines in mammalian mRNA are N6-methyladenosine (m6A) methylated. Lack of m6A methylation is lethal
in mammals. We have shown that mRNA m6A methylation is critical to neuronal functions and enriched in AD-
related transcripts. This methylation can be recognized by reader proteins such as YTHDF1, YTHDF2 and
YTHDF3. The mRNA m6A methylation and its binding by different reader proteins play critical roles in cellular
RNP granule dynamics, which dramatically affect mRNA metabolism and translation.
We have observed notable changes of YTHDF proteins in AD brain tissues versus normal controls. In this
Supplement, we hypothesize that aberrant YTHDF levels affect both methylation-dependent and methylation-
independent stabilization of human mRNAs. This effect may also alter cellular RNP granule dynamics, leading
to aberrant mRNA metabolism and translation in AD brains. To test this hypothesis, we will conduct a quantitative
genome-wide brain m6A mapping using a newly developed m6A-SAC-seq protocol to identify m6A alterations
associated with AD. We will also map precise RNA binding sites of all three YTHDF proteins in AD samples and
controls. By integrating RNA-seq data, m6A map and YTHDF binding results we will evaluate effects of YTHDF
downregulation on mRNA stability and cellular RNP granule changes. These changes may underline AD
pathogenesis in patients and may suggest new intervention strategies.

## Key facts

- **NIH application ID:** 10690993
- **Project number:** 3RM1HG008935-08S1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** CHUAN HE
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $424,102
- **Award type:** 3
- **Project period:** 2016-09-27 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690993

## Citation

> US National Institutes of Health, RePORTER application 10690993, Effects of mRNA m6A methylation and its YTHDF reader proteins on human AD mRNA homeostasis (3RM1HG008935-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690993. Licensed CC0.

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