# TAFopathies Result from Derangements in Transcriptional Control of Metabolism

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2021 · $31,970

## Abstract

Project Summary
Intellectual disability is a disabling neurodevelopmental disorder that affects 2-3% of the general population.
Often times, these intellectual disabilities are accompanied by additional developmental abnormalities. These
syndromic forms of intellectual disability frequently have a genetic basis. Recent studies have identified a
subset of intellectual disability patients with pathogenic variants in key components of the TATA-binding protein
associated factors (TAFs). These patients also have craniofacial defects and congenital heart disease. This
syndrome has been termed as a TAFopathy and includes mutations in TATA binding protein (TBP), TAF1,
TAF2, and TAF6. Through a forward genetic screen, we have recovered a lethal nonsense mutation in TAF5.
Mutant embryos have craniofacial hypoplasia, ventricular hypoplasia, and heart failure at 96 hours post
fertilization. CRISPR/Cas9 mediated gene editing revealed that this phenotype was recapitulated in TAF1 KO
and TAF5 KO embryos. TAF5 KOs show significant metabolic dysfunction that may precede the anatomical
defects observed at 96 hours post fertilization. Together, these findings support a regulatory role for TAFs in
coordinating transcriptional activation of metabolic programming during embryogenesis. The TAFs form the
general transcription factor TFIID, which recruits RNA Polymerase II to form the preinitation complex at sites of
transcription. Studies have shown that individual TAFs are not necessary for general transcription. Other
studies have identified functional domains of TAF1 that activate transcription through interactions with TBP and
enhancer elements that are sufficient to recruit RNA Polymerase II to sites of transcription. In conjunction with
our data showing metabolic dysfunction, we hypothesize that TAFs regulate metabolic programs by linking
enhancers and promoters of metabolic genes through TFIID assembly. Our current efforts are focused towards
completing our phenotypic characterization of TAF1 KOs and TAF5 KOs with respect to craniofacial- and
neuro-development. We plan to use innovative and cutting-edge techniques, including x-ray microscopy, RNA-
Scope in situ hybridization, mitochondrial respiration assays, ChIP-seq, and Hi-C to achieve this goal. The data
obtained will help us elucidate basic disease mechanisms of TAFopathy. These findings would also indicate a
secondary function for general transcription factors to regulate metabolic programming during embryogenesis.
.

## Key facts

- **NIH application ID:** 10314285
- **Project number:** 1F31HD106710-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jamison Leid
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,970
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314285

## Citation

> US National Institutes of Health, RePORTER application 10314285, TAFopathies Result from Derangements in Transcriptional Control of Metabolism (1F31HD106710-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10314285. Licensed CC0.

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