Deletion of taf1 and taf5 in zebrafish capitulate cardiac and craniofacial abnormalities associated with TAFopathies through perturbations in metabolism

Jamison Leid; Ryan Gray; Peter Rakita; Andrew L Koenig; Rohan Tripathy; James A J Fitzpatrick; Charles Kaufman; Lilianna Solnica-Krezel; Kory J Lavine

doi:10.1242/bio.059905

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Deletion of taf1 and taf5 in zebrafish capitulate cardiac and craniofacial abnormalities associated with TAFopathies through perturbations in metabolism

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Deletion of taf1 and taf5 in zebrafish capitulate cardiac and craniofacial abnormalities associated with TAFopathies through perturbations in metabolism

Jamison Leid, Ryan Gray, Peter Rakita, Andrew L Koenig, Rohan Tripathy, James A J Fitzpatrick, Charles Kaufman, Lilianna Solnica-Krezel and Kory J Lavine

Biology open, Vol.12(7), bio059905

07/15/2023

DOI: 10.1242/bio.059905

PMCID: PMC10354717

PMID: 37746814

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Abstract

Intellectual disability is a neurodevelopmental disorder that affects 2-3% of the general population. Syndromic forms of intellectual disability frequently have a genetic basis and are often accompanied by additional developmental anomalies. Pathogenic variants in components of TATA-binding protein associated factors (TAFs) have recently been identified in a subset of patients with intellectual disability, craniofacial hypoplasia, and congenital heart disease. This syndrome has been termed as a TAFopathy and includes mutations in TATA binding protein (TBP), TAF1, TAF2, and TAF6. The underlying mechanism by which TAFopathies give rise to neurodevelopmental, craniofacial, and cardiac abnormalities remains to be defined. Through a forward genetic screen in zebrafish, we have recovered a recessive mutant phenotype characterized by craniofacial hypoplasia, ventricular hypoplasia, heart failure at 96 h post-fertilization and lethality, and show it is caused by a nonsense mutation in taf5. CRISPR/CAS9 mediated gene editing revealed that these defects where phenocopied by mutations in taf1 and taf5. Mechanistically, taf5-/- zebrafish displayed misregulation in metabolic gene expression and metabolism as evidenced by RNA sequencing, respiration assays, and metabolite studies. Collectively, these findings suggest that the TAF complex may contribute to neurologic, craniofacial, and cardiac development through regulation of metabolism.

Animals

Craniofacial Abnormalities - genetics

Heart

Intellectual Disability

Mutation

TATA-Binding Protein Associated Factors - genetics

Transcription Factor TFIID - genetics

Zebrafish

Zebrafish Proteins - genetics

Details

Title: Subtitle: Deletion of taf1 and taf5 in zebrafish capitulate cardiac and craniofacial abnormalities associated with TAFopathies through perturbations in metabolism
Creators: Jamison Leid - Washington University in St. Louis
Ryan Gray - The University of Texas at Austin
Peter Rakita - Washington University in St. Louis
Andrew L Koenig - Washington University in St. Louis
Rohan Tripathy - Washington University in St. Louis
James A J Fitzpatrick - Washington University in St. Louis
Charles Kaufman - Washington University in St. Louis
Lilianna Solnica-Krezel - Washington University in St. Louis
Kory J Lavine - Washington University in St. Louis
Resource Type: Journal article
Publication Details: Biology open, Vol.12(7), bio059905
DOI: 10.1242/bio.059905
PMID: 37746814
PMCID: PMC10354717
NLM abbreviation: Biol Open
ISSN: 2046-6390
eISSN: 2046-6390
Grant note: R21 AI148877 / NIAID NIH HHS R01 HL139714 / NHLBI NIH HHS T32 HL125241 / NHLBI NIH HHS UL1 TR000448 / NCATS NIH HHS R35 GM118179 / NIGMS NIH HHS R35 HL161185 / NHLBI NIH HHS P30 CA091842 / NCI NIH HHS P30 DK020579 / NIDDK NIH HHS P30 DK056341 / NIDDK NIH HHS R01 HL151078 / NHLBI NIH HHS
Language: English
Date published: 07/15/2023
Academic Unit: Stead Family Department of Pediatrics
Record Identifier: 9985161457302771

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