Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Van-Gils, Julien; Magdinier, Frédérique; Fergelot, Patricia; Lacombe, Didier

doi:10.3390/genes12070968

Cited by 46 publications

(47 citation statements)

References 173 publications

(326 reference statements)

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“…36 Mutations in CREBBP are far more common than mutations in EP300 in Rubinstein-Taybi syndrome, and disease presentation overall is similar but generally more mild with EP300 mutations. 36 Rubinstein-Taybi syndrome can include cardiovascular developmental defects, including smooth muscle pathologies such as patent ductus arteriosus and aortic coarctation. 37 Given the relatively low numbers of cases, it is not yet known whether the cardiovascular disease presentation differs with mutations in CREBBP versus EP300 .…”

Section: Discussionmentioning

confidence: 99%

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity

et al. 2022

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Background: Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methylcytosine dioxygenase TET2 acting as a master regulator of smooth muscle cell phenotype. The histone acetyl-transferases p300 and CREB-binding protein (CBP) are highly homologous and often considered to be interchangeable, and their roles in smooth muscle cell phenotypic regulation are not known. Methods: We assessed the roles of p300 and CBP in human VSMC with knockdown, in inducible smooth muscle–specific knockout mice (inducible knockout [iKO]; p300 iKO or CBP iKO ), and in samples of human intimal hyperplasia. Results: P300, CBP, and histone acetylation were differently regulated in VSMCs undergoing phenotypic switching and in vessel remodeling after vascular injury. Medial p300 expression and activity were repressed by injury, but CBP and histone acetylation were induced in neointima. Knockdown experiments revealed opposing effects of p300 and CBP in the VSMC phenotype: p300 promoted contractile protein expression and inhibited migration, but CBP inhibited contractile genes and enhanced migration. p300 iKO mice exhibited severe intimal hyperplasia after arterial injury compared with controls, whereas CBP iKO mice were entirely protected. In normal aorta, p300 iKO reduced, but CBP iKO enhanced, contractile protein expression and contractility compared with controls. Mechanistically, we found that these histone acetyl-transferases oppositely regulate histone acetylation, DNA hydroxymethylation, and PolII (RNA polymerase II) binding to promoters of differentiation-specific contractile genes. Our data indicate that p300 and TET2 function together, because p300 was required for TET2-dependent hydroxymethylation of contractile promoters, and TET2 was required for p300-dependent acetylation of these loci. TET2 coimmunoprecipitated with p300, and this interaction was enhanced by rapamycin but repressed by platelet-derived growth factor (PDGF) treatment, with p300 promoting TET2 protein stability. CBP did not associate with TET2, but instead facilitated recruitment of histone deacetylases (HDAC2, HDAC5) to contractile protein promoters. Furthermore, CBP inhibited TET2 mRNA levels. Immunostaining of cardiac allograft vasculopathy samples revealed that p300 expression is repressed but CBP is induced in human intimal hyperplasia. Conclusions: This work reveals that p300 and CBP serve nonredundant and opposing functions in VSMC phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with TET2 or HDACs. Targeting specific histone acetyl-transferases may hold therapeutic promise for cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity

et al. 2022

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“…Recently, de novo pathogenic variants in the HX repeat region of AUTS2 were described in patients with a phenotype overlapping with Rubinstein-Taybi syndrome (Liu et al, 2021). Rubinstein-Taybi syndrome (RSTS, OMIM 180849 and OMIM 613684) is a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorders, microcephaly, facial dysmorphism, growth retardation, large thumbs and hallux and a variable degree of additional malformations and symptoms (reviewed in Van Gils et al, 2021). The underlying cause of RSTS are pathogenic variants in EP300 and CREBBP (Petrij et al, 1995;Roelfsema et al, 2005).…”

Section: Auts2 Has Nuclear and Cytoplasmic Functions Which May Be Shared By Fbrsl1mentioning

confidence: 99%

Comparing a Novel Malformation Syndrome Caused by Pathogenic Variants in FBRSL1 to AUTS2 Syndrome

Pauli

Berger

Ufartes

et al. 2021

Front. Cell Dev. Biol.

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Truncating variants in specific exons of Fibrosin-like protein 1 (FBRSL1) were recently reported to cause a novel malformation and intellectual disability syndrome. The clinical spectrum includes microcephaly, facial dysmorphism, cleft palate, skin creases, skeletal anomalies and contractures, postnatal growth retardation, global developmental delay as well as respiratory problems, hearing impairment and heart defects. The function of FBRSL1 is largely unknown, but pathogenic variants in the FBRSL1 paralog Autism Susceptibility Candidate 2 (AUTS2) are causative for an intellectual disability syndrome with microcephaly (AUTS2 syndrome). Some patients with AUTS2 syndrome also show additional symptoms like heart defects and contractures overlapping with the phenotype presented by patients with FBRSL1 mutations. For AUTS2, a dual function, depending on different isoforms, was described and suggested for FBRSL1. Both, nuclear FBRSL1 and AUTS2 are components of the Polycomb subcomplexes PRC1.3 and PRC1.5. These complexes have essential roles in developmental processes, cellular differentiation and proliferation by regulating gene expression via histone modification. In addition, cytoplasmic AUTS2 controls neural development, neuronal migration and neurite extension by regulating the cytoskeleton. Here, we review recent data on FBRSL1 in respect to previously published data on AUTS2 to gain further insights into its molecular function, its role in development as well as its impact on human genetics.

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“…Rubinstein–Taybi syndrome (RSTS; OMIM # 180849) is a rare congenital anomaly described in 1963, characterized by postnatal growth deficiency, microcephaly, broad thumbs, halluces dysmorphic facial features, and mild to severe intellectual disability. Facial features include mild micrognathia, highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, and characteristic grimacing or abnormal smile 1–3 . The prevalence of RSTS is estimated to be 1 in 100,000 to 125,000 living newborn infants 1 .…”

Section: Introductionmentioning

confidence: 99%

“…Although RSTS usually occurs sporadically, as a de novo mutation in the family, it can be inherited as an autosomal dominant disorder 1,3 . RSTS shows microdeletions and chromosomal breakpoints within the CBP locus (16p13.3) or presents mutations in the EP300 gene located on chromosome 22q13.2.…”

Section: Introductionmentioning

confidence: 99%

“…CBP is a transcriptional coactivator that plays an essential role in chromatin remodeling, signaling pathways, and basic cellular functions, such as DNA repair, cell growth, differentiation, and tumor suppression. Both CBP and p300, a highly related and widely expressed protein, are crucial for healthy embryonic development 1–3,5 . Genetic tests are helpful in diagnosing RSTS, but most cases are currently diagnosed based on clinical features 2,6 …”

Section: Introductionmentioning

confidence: 99%

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Oral and cephalometric study in Brazilian Rubinstein–Taybi syndrome patients

Martins

Roussen

Rezende

et al. 2021

Special Care in Dentistry

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Objective The purpose of this study was to describe a detailed investigation of craniofacial and dental characteristics in a group of Brazilian Rubinstein–Taybi syndrome (RSTS) patients. Methods and results Thirteen RSTS patients treated in a special care dental clinic after 10 years were studied. Panoramic radiographs were obtained from all patients, and cephalometric analysis was performed in eight patients. Five male and eight white female patients with a median age of 11.7 years were analyzed. All the RSTS patients were mouth breathers and presented malocclusion, transverse hypoplastic maxilla, nine subjects (9/13; 69.2%) had posterior crossbite, and eight (61.53%) exhibited talon cusps. Most patients presented class II skeletal pattern and were brachycephalic. Regarding systemic disorders, one patient (7.69%) reported seizure episodes during childhood, and four patients (30.76%) presented heart valve disorders. All patients presented reduced attention span, low intolerance to dental interventions, impulsiveness, and irritability. Conclusions Since RSTS exhibits oral and skeletal changes, early dental treatment is essential for these patients. Dentists must be aware of medical problems related to heart disease and persist in conditioning techniques to obtain cooperation and avoid dental care under general anesthesia.

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Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Cited by 46 publications

References 173 publications

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity

Comparing a Novel Malformation Syndrome Caused by Pathogenic Variants in FBRSL1 to AUTS2 Syndrome

Oral and cephalometric study in Brazilian Rubinstein–Taybi syndrome patients

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