Research: Rescuing lung development through embryonic inhibition of histone acetylation

Sci Transl Med

. 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 Stokes 1Zhuowei Li 1Nicole Talaba 1William Genthe 2Maria B Brix 2Betty Pham 1Mark D Wienhold 3Gracia Sandok 2Rebecca Hernan 4Julia Wynn 4Haiyang Tang 5Diana M Tabima 6Allison Rodgers 7Timothy A Hacker 7Naomi C Chesler 8Pan Zhang 9Rabi Murad 9Jason X-J Yuan 10Yufeng Shen 11Wendy K Chung 12David J McCulley 1

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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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