Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Kou, Yan; Rousseau, Justine; Machol, Keren; Cross, Laura; Agre, Katherine; Gibson, Cynthia Forster; Goverde, Angelique J.; Engleman, Kendra; Verdin, Hannah; Baere, Elfride De; Potocki, Lorraine; Zhou, Dihong; Cadieux-Dion, Maxime; Bellus, Gary A.; Wagner, Monisa; Hale, Rebecca J.; Esber, Natacha; Riley, Alan; Solomon, Benjamin D.; Cho, Megan T.; McWalter, Kirsty; Eyal, Roy; Hainlen, Meagan K.; Mendelsohn, Bryce A.; Porter, Hillary M.; Lanpher, Brendan C.; Lewis, Andrea M.; Savatt, Juliann M.; Thiffault, Isabelle; Callewaert, Bert; Campeau, Philippe M.; Yang, Xiang

doi:10.1126/sciadv.aax0021

Cited by 68 publications

(93 citation statements)

References 61 publications

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“…H3K23pr was also recently identified. Of note, cardiac anomalies are present in a subset of patients with deficient H3K23pr catalyzed by BRPF1-KAT6 complexes [98]. Therefore, histone propionylation may critically contribute to cardiovascular homeostasis and diseases.…”

Section: Propionate and Propionylationmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure. Clinical Science (2020) 134 657-676 https://doi.org/10.1042/CS20200128 cofactors in certain protein acylations, such as propionylation [14], malonylation [15], butyrylation [14], 2-hydroxyisobutyrylation [16], β-hydroxybutyrylation [17], crotonylation [18], succinylation [19], and glutarylation [20]. These discoveries give us a deeper understanding of PTM. Among PTMs, protein acetylation is the earliest discovered and most studied. Similar to protein acetylation, various studies have shown that these newly discovered PTMs are also involved in physiological and pathophysiological processes, including cardiovascular homeostasis.Here in this review, we will summarize SCFAs, protein acylations, and their emerging roles in CVDs, including atherosclerosis, hypertension, and heart failure. The metabolic pattern and FAs in CVDsThe heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart. The embryonic heart depends primarily on glycolysis as well as lactate oxidation to produce energy [21]. The newborn and adult heart shift toward the remarkable utilization of FAs to meet cardiac energy demand [5,9]. In failing hearts, a decrease in FA oxidation and an increase in glycolysis are critically involved in cardiac dysfunction [22]. As thus, the metabolic pattern is essential for maintaining cardiac and vascular functions.Diabetes, hypertension, and obesity contribute to heart failure syndrome. Accumulating evidence suggests that hypertension, ischemic hearts, and heart failure induce a shift in substrate toward the remarkable utilization of glucose to generate energy. Despite this shift, the FA oxidation remains to make much energy for the diseased heart [23]. Since FAs are the predominant substrates for cardiomyocytes, alterations in FA metabolism have been implicated as causal in cardiac diseases. FAs within cells and in the circulation are critically involved in cardiometabolic diseases. CVDs are closely associated with lifestyle and metabolic status, which affect circul...

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Section: Propionate and Propionylationmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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“…BRPF1 encodes a component of the MOZ/MORF which has a histone H3 acetyltransferase activity. The frameshift variant we detected should alter the interaction with KAT6A and KAT6B thus impairing BRPF1 in activating KAT6A for H3K23 propionylation, as demonstrated for IDDDFP patients with variants comparable to that of patient 22 (Yan 2020). Not by chance, de novo truncating mutations in KAT6B, which cause a spectrum of disorders, include, although rarely, C1M (Kennedy 2019), and more frequently craniosynostosis which in turn may cause Chiari malformation (Bashir 2017).…”

Section: W3 Histone Acetyltransferasesmentioning

confidence: 66%

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes

et al. 2020

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Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

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“…Many members of the family Lachnospiraceae are known as butyrate-producing bacteria (30,31). A previous study revealed that butyrate alleviated the acylation deficiency (caused by the mutations of in the bromodomain-and PHD finger-containing protein 1 Brpf1 gene) of histone H3 at lysine 23 in mouse embryos and fibroblasts and human embryonic kidney 293 cells, and this deficiency was also found in children with neurodevelopmental delay (32). This study suggests that butyrate may alleviate the severity of neurodevelopmental delay in children.…”

Section: Discussionmentioning

confidence: 98%