Rescuing lung development through embryonic inhibition of histone acetylation

doi:10.1126/scitranslmed.adc8930

. 2024 Jan 31;16(732):eadc8930.

doi: 10.1126/scitranslmed.adc8930. Epub 2024 Jan 31.

Rescuing lung development through embryonic inhibition of histone acetylation

Giangela Stokes¹, Zhuowei Li¹, Nicole Talaba¹, William Genthe², Maria B Brix², Betty Pham¹, Mark D Wienhold³, Gracia Sandok², Rebecca Hernan⁴, Julia Wynn⁴, Haiyang Tang⁵, Diana M Tabima⁶, Allison Rodgers⁷, Timothy A Hacker⁷, Naomi C Chesler⁸, Pan Zhang⁹, Rabi Murad⁹, Jason X-J Yuan¹⁰, Yufeng Shen¹¹, Wendy K Chung¹², David J McCulley¹

Affiliations

¹ Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
² Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ 490 BioTech Inc., Knoxville, TN 37996, USA.
⁴ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong, China.
⁶ Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁷ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁸ Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center and Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA.
⁹ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
¹⁰ Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹¹ Department of Systems Biology, Department of Biomedical Informatics, and JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹² Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

PMID: 38295182
DOI: 10.1126/scitranslmed.adc8930

Rescuing lung development through embryonic inhibition of histone acetylation

Giangela Stokes et al. Sci Transl Med. 2024.

. 2024 Jan 31;16(732):eadc8930.

doi: 10.1126/scitranslmed.adc8930. Epub 2024 Jan 31.

Authors

Affiliations

¹ Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
² Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ 490 BioTech Inc., Knoxville, TN 37996, USA.
⁴ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong, China.
⁶ Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁷ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁸ Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center and Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA.
⁹ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
¹⁰ Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹¹ Department of Systems Biology, Department of Biomedical Informatics, and JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹² Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

PMID: 38295182
DOI: 10.1126/scitranslmed.adc8930

Abstract

A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying mechanisms are unclear. We identified loss-of-function sequence variants in the epigenomic regulator gene SIN3A in two patients with complex CDH. Tissue-specific deletion of Sin3a in mice resulted in defects in diaphragm development, lung hypoplasia, and pulmonary hypertension, the cardinal features of CDH and major causes of CDH-associated mortality. Loss of SIN3A in the lung mesenchyme resulted in reduced cellular differentiation, impaired cell proliferation, and increased DNA damage. Treatment of embryonic Sin3a mutant mice with anacardic acid, an inhibitor of histone acetyltransferase, reduced DNA damage, increased cell proliferation and differentiation, improved lung and pulmonary vascular development, and reduced pulmonary hypertension. These findings demonstrate that restoring the balance of histone acetylation can improve lung development in the Sin3a mouse model of CDH.

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Rescuing lung development through embryonic inhibition of histone acetylation

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Rescuing lung development through embryonic inhibition of histone acetylation

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