Joo-Hye C. Park

Neuroscience Institute

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Elmer Guzman

University of California, Santa Barbara

Shi‐Yan Ng

Institute of Molecular and Cell Biology

Kenneth S. Kosik

University of California, Santa Barbara

Hao Wu

Xi'an Jiaotong University

Daniel Bridges

University of California, Santa Barbara

Morgane Audouard

University of California, Santa Barbara

Ulrika Felldin

Uppsala University

Xiaojun Lian

Pennsylvania State University

Sorina Mihaela Papuc

Institutul National Victor Babes

Bing Lim

Sana Biotechnology (United States)

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Harvard University

Massachusetts General Hospital

Karolinska Institutet

University of Hong Kong

University of California, Santa Barbara

Neuroscience Institute

Agency for Science, Technology and Research

Institutul National Victor Babes

Clinical Emergency Hospital Bucharest

National Institute of Pathology

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Correction: Corrigendum: Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells

Nature Communications (2016)

Boon-Seng Soh Shi‐Yan Ng Hao Wu Kristina Buac Joo-Hye C. Park

Nature Communications 7: Article number: 10774 (2016); Published: 8 March 2016; Updated: 19 July 2016. The affiliation details for Boon-Seng Soh, Lei Bu and Ronald A. Li are incorrect in this Article. The correct addresses of these authors are listed below: Boon-Seng Soh Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA; Li Dak-Sum Research Centre-HKU-Karolinska Institutet Collaboration on Regenerative Medicine, University of Hong Kong, Hong Kong, China and Department of Cell and Molecular Biology and Medicine, Karolinska Institute, Stockholm S-171 77, Sweden.

Stem cell biology

10.1038/ncomms12118

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Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways

Human Molecular Genetics (2016)

Matthew A. Lalli Jiwon Jang Joo-Hye C. Park Yidi Wang Elmer Guzman

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams–Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.

Haploinsufficiency

Neural Development

Chromatin immunoprecipitation

Williams Syndrome

Chromosome conformation capture

10.1093/hmg/ddw010

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Citations (69)