Williams syndrome is an epigenome-regulator disease

Kitagawa, Hirochika; Fujiki, Ryoji; Yoshimura, Kimihiro; Oya, Hiroyuki; Kato, Shigeaki

doi:10.1507/endocrj.k10e-393

Cited by 18 publications

(16 citation statements)

References 45 publications

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“…33,34 Furthermore, the deficiency of Williams syndrome transcription factor (WSTF), a nuclear protein codified by the Williams-Beuren Syndrome Chromosome Region 1 gene (WBSCR1, OMIM *603431), may play a role in the aetiology of hypercalcaemia in WBS, 35 because of evidence of abnormal chromatin remodelling activity. 36 Other authors suspect that the haploinsufficiency of the general transcription factor II-I gene (GTF2I, *601679) may have an effect on the impaired calcium metabolism. This gene encodes TFII-I, a multifunctional transcription factor 37 that acts as a negative regulator of calcium entry by suppressing the surface accumulation of transient receptor potential C3 (TRPC3) channels.…”

Section: Discussionmentioning

confidence: 99%

Bone mineral status and metabolism in patients with Williams-Beuren syndrome

Stagi¹,

Manoni²,

Scalini³

et al. 2016

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ObJECTIvE: To evaluate bone mineral status and metabolism in a cohort of patients with Williams-beuren syndrome (WbS). paTIENTS: Thirty-one children (15 females, 16 males; mean age 9.6±2.74 years) and 10 young adults (6 females, 4 males; mean age 21.4±5.11 years) with WbS were cross-sectionally evaluated and compared with two age-, sex-, and body-sizematched paediatric (155 subjects, 75 females and 80 males; mean age 9.7±2.93 years) and adult (50 subjects, 30 females and 20 males; mean age 22.3±5.42 years) healthy controls. mEaSUREmENTS: We evaluated ionised and total calcium, phosphate, parathyroid hormone (pTh), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, bone alkaline phosphatase levels, and urinary deoxypyridinoline concentrations. We also calculated the phalangeal amplitudedependent speed of sound (aD-SoS) and the bone transmission time (bTT) z-scores. RESUlTS: WbS patients showed a significantly reduced aD-SoS z-score (p <0.001) and bTT z-score (p <0.001) compared with the controls. This finding persisted when we divided the sample into paediatric and adult patients. WbS patients also had significantly higher ionised (p <0.001) and total calcium (p <0.001) levels as well as higher pTh levels (p <0.001) compared with the controls. Furthermore, WbS children and adolescents had significantly lower serum osteocalcin levels (p <0.001) and urinary deoxypyridinoline concentrations (p <0.001) than controls. CONClUSIONS: WbS subjects exhibit a significant reduction in bone mineral status and impaired bone metabolism. These findings point to the need for close monitoring of WbS patients.

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Section: Discussionmentioning

confidence: 99%

Bone mineral status and metabolism in patients with Williams-Beuren syndrome

Stagi¹,

Manoni²,

Scalini³

et al. 2016

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“…These interactions result in specific epigenetic modifications of promoters of cardiac specific genes, thereby regulating gene expression during cardiac lineage specification. 144,145 The involvement of epigenetic mechanisms in cardiac differentiation has been revealed by mutations of several chromatin modifiers, such as ATP-dependent chromatin remodeling complex CHD7, 146 WSTF (Williams syndrome transcription factor), 147 and histone H3K36 methyltransferase Wolf-Hirschhorn syndrome candidate 1 (WHSC1). 148 All of these factors are also involved in the pathogenesis of human heart diseases.…”

Section: Epigenetic Regulation Of Cardiac Progenitor Cell Differentiamentioning

confidence: 99%

Epigenetic Modifications of Stem Cells

Zhou

Kim

Yuan

et al. 2011

Circulation Research

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Stem cells of all types are characterized by the ability to self-renew and to differentiate. Multiple lines of evidence suggest that both maintenance of stemness and lineage commitment, including determination of the cardiomyogenic lineage, are tightly controlled by epigenetic mechanisms such as DNA methylation, histone modifications, and ATP-dependent chromatin remodeling. Epigenetic mechanisms are intrinsically reversible, interdependent, and highly dynamic in regulation of chromatin structure and specific gene transcription programs, thereby contributing to stem cell homeostasis. Here, we review the current understanding of epigenetic mechanisms involved in regulation of stem cell self-renewal and differentiation and in the control of cardiac progenitor cell commitment during heart development. Further progress in this area will help to decipher the epigenetic landscape in stem and progenitor cells and facilitate manipulation of stem cells for regenerative applications.

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“…Fourth, might WSTF and Eya share other substrates? WSTF plays important roles in chromatin assembly, remodeling, and transcriptional regulation, and its loss-of-function phenotypes suggest broad developmental requirements in heart, thymus, neural crest, kidney, tooth, and brain (79)(80)(81). Whether its tyrosine kinase is relevant in those contexts and what substrates might be targeted are open questions, but it is tempting to speculate that this unconventional kinase might pair up with the unconventional Eya phosphatase to regulate a variety of substrates.…”

Section: The Quest For Eya Tyrosine Phosphatase Substratesmentioning

confidence: 99%

Multiple Functions of the Eya Phosphotyrosine Phosphatase

Rebay

2016

Molecular and Cellular Biology

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Eyes absent (Eya), a protein conserved from plants to humans and best characterized as a transcriptional coactivator, is also the prototype for a novel class of eukaryotic aspartyl protein tyrosine phosphatases. This minireview discusses recent breakthroughs in elucidating the substrates and cellular events regulated by Eya's tyrosine phosphatase function and highlights some of the complexities, new questions, and surprises that have emerged from efforts to understand how Eya's unusual multifunctionality influences developmental regulation and signaling. Drosophila Eyes absent (Eya), the founding member of the Eya family, was molecularly defined in 1993 as a novel nuclear protein with essential roles in retinal cell survival and differentiation (1). Four years later, three key findings heightened interest in Eya family proteins. First, three mammalian Eya homologues, Eya1 Eya2, and Eya3, were identified and found to be expressed in the lens and nasal placodes, raising the possibility that the developmental program of eye specification is conserved between invertebrates and mammals (2, 3); the fourth vertebrate Eya gene, Eya4, was identified 2 years later (4). Functional conservation of Eya proteins was further emphasized by the demonstration that expression of murine Eya2 partially restores eye development in Drosophila eya mutants (5). Second, the discovery that loss-offunction mutations in Eya1 produced the ear, kidney and craniofacial defects associated with the autosomal-dominant disease branchio-oto-renal (BOR) syndrome (6-8) highlighted Eya's critical and pleiotropic roles in human development and disease. Third, parallel studies in Drosophila and in mammalian cultured cells revealed a molecular function for Eya as a transcriptional coactivator (5, 9-12). Eya is recruited to transcriptional complexes via a direct interaction between its highly conserved ϳ270-amino-acid (aa) C-terminal motif, the Eya domain (ED) (Fig. 1), and Six family homeodomain DNA binding proteins. Together, Eya and Six operate as a composite transcription factor, with Six providing DNA binding specificity and the N-terminal half of Eya conferring transactivation.In addition to the many similarities, mammalian and Drosophila Eya proteins show a striking difference in subcellular localization. In contrast to Drosophila Eya, which appears constitutively nuclear (13), mammalian Eya proteins show significant cytoplasmic accumulation and rely on binding to Six for nuclear recruitment and retention (11,(13)(14)(15)(16)(17)(18)(19)(20). Although initially dismissed as reflecting two slightly different mechanisms for regulating Eyamediated transcriptional events, in retrospect, as discussed later in this minireview, this observation seems to have foretold a much more profound functional divergence between mammalian and fly Eya proteins.Subsequent molecular genetic studies positioned Eya and Six as central players within a conserved network of transcription factors that is referred to as the retinal determination (RD) network (reviewed in refer...

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Williams syndrome is an epigenome-regulator disease

Cited by 18 publications

References 45 publications

Bone mineral status and metabolism in patients with Williams-Beuren syndrome

Bone mineral status and metabolism in patients with Williams-Beuren syndrome

Epigenetic Modifications of Stem Cells

Multiple Functions of the Eya Phosphotyrosine Phosphatase

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