Rescuing lung development through embryonic inhibition of histone acetylation.
Giangela StokesZhuowei LiNicole TalabaWilliam GentheMaria B BrixBetty PhamMark D WienholdGracia SandokRebecca HernanJulia WynnHaiyang TangDiana M TabimaAllison RodgersTimothy A HackerNaomi C CheslerPan ZhangRabi MuradJason X-J YuanYufeng ShenWendy K ChungDavid J McCulleyPublished in: Science translational medicine (2024)
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.
Keyphrases
- pulmonary hypertension
- dna damage
- cell proliferation
- copy number
- dna methylation
- oxidative stress
- pulmonary artery
- cardiovascular disease
- dna repair
- cell cycle
- type diabetes
- genome wide
- coronary artery disease
- amino acid
- signaling pathway
- adipose tissue
- metabolic syndrome
- pi k akt
- acute respiratory distress syndrome
- smoking cessation