# FMRP Regulation of Gene Expression

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $598,708

## Abstract

The Fragile X Syndrome (FXS) is an inherited neurological disorder on the autism spectrum that is caused by
expansion of CGG triplets in the 5' untranslated region (UTR) of FMR1, leading to its epigenetic silencing. In the
absence of the FMR1 gene product FMRP, protein synthesis in the brain is excessive, which is correlated with
several manifestations of the disorder including cognitive impairment, developmental delays, social deficits,
seizures, etc. Elevated protein synthesis likely drives several of these pathophysiologies, thereby underscoring
the importance of understanding FMRP-regulated translation. FMRP is an RNA binding protein that represses
translation and does so, at least in part, by impeding ribosome translocation on specific mRNAs. How FMRP
could stall ribosomes is unclear, although reconstitution experiments suggest that it could bind the ribosome and
block interactions with essential translation factors. Our studies focused initially on identifying the mRNAs that
are bound with FMRP-stalled ribosomes. By modifying transcriptome-wide ribosome profiling to determine rates
of ribosome transit in the mouse hippocampus, we find that thousands of mRNAs are bound by slow moving or
nearly completely stalled ribosomes. FMRP in particular is necessary to stall ribosomes on a number of specific
mRNAs including several that, surprisingly, code for epigenetic and transcription factors. One of these mRNAs
bound by FMRP-stalled ribosomes encodes SETD2, which catalyzes the chromatin mark H3K36me3 and which
is elevated ~2.5 fold in Fmr1-deficient hippocampus. ChIP-seq demonstrates that in the absence of FMRP,
H3K36me3 is rearranged on chromatin including in gene bodies where it modulates pre-mRNA processing. We
find substantial mis-regulation of RNA slicing, particularly exon skipping events, which strongly link FXS to
autism. Based on these and other data, we propose three multi-part specific aims: 1) determine whether FMRP
stalls ribosomes at specific sites on mRNA, occurs in excitatory neurons, is alleviated by synaptic activity, and
takes place in cell bodies and/or dendrites; 2) investigate whether depletion of SETD2 ameliorates FXS
pathophysiology in model mice; 3) determine whether exon skipping occurs in excitatory neurons, microexon
skipping in the autism risk gene CPEB4 links FXS to autism, and alteration of factors that mediate exon skipping
can rescue biochemical features of FXS and autism.

## Key facts

- **NIH application ID:** 10476366
- **Project number:** 5R01GM135087-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** KIMBERLY M. HUBER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $598,708
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476366

## Citation

> US National Institutes of Health, RePORTER application 10476366, FMRP Regulation of Gene Expression (5R01GM135087-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10476366. Licensed CC0.

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