Transcriptional readthrough at <i>Atf4</i> locus suppresses <i>Rps19bp1</i> and impairs heart development
We found that the downregulation of Rps19bp1, not the loss of ATF4 function, underlies the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 KO models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.
Authors
- Christopher M. Adams (ORCID: https://orcid.org/0000-0002-5795-7212)
- Zengming Zhang (ORCID: https://orcid.org/0000-0001-8245-9955)
- Mao Ye (ORCID: https://orcid.org/0000-0002-4798-1825)
- Yusu Gu (ORCID: https://orcid.org/0000-0002-9543-8472)
- Xiaohai Zhou (ORCID: https://orcid.org/0000-0002-0987-0374)
- Zhengyu Liang (ORCID: https://orcid.org/0000-0002-3307-0959)
- Sylvia Μ. Evans (ORCID: https://orcid.org/0000-0001-5035-3697)
- Tongbin Wu (ORCID: https://orcid.org/0000-0001-6232-3268)
- Zeyu Chen (ORCID: https://orcid.org/0000-0003-3442-4162)
- Ju Chen (ORCID: https://orcid.org/0000-0001-7674-4776)
- Danni Chen (ORCID: https://orcid.org/0000-0002-6003-8284)
- Fhujjen Barroga
Institutions
- Mayo Clinic (US)
- University of California San Diego (US)
- Masonic Medical Research Laboratory (US)
- Human Longevity (United States) (US)
- University of Montana (US)
Publication Details
- Journal
- Cardiovascular Research
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1093/cvr/cvaf237
- Citations
- 2
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 1.61