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The nuclear localization pattern and interaction partners of GTF2IRD1 demonstrate a role in chromatin regulation

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Abstract

GTF2IRD1 is one of the three members of the GTF2I gene family, clustered on chromosome 7 within a 1.8 Mb region that is prone to duplications and deletions in humans. Hemizygous deletions cause Williams–Beuren syndrome (WBS) and duplications cause WBS duplication syndrome. These copy number variations disturb a variety of developmental systems and neurological functions. Human mapping data and analyses of knockout mice show that GTF2IRD1 and GTF2I underpin the craniofacial abnormalities, mental retardation, visuospatial deficits and hypersociability of WBS. However, the cellular role of the GTF2IRD1 protein is poorly understood due to its very low abundance and a paucity of reagents. Here, for the first time, we show that endogenous GTF2IRD1 has a punctate pattern in the nuclei of cultured human cell lines and neurons. To probe the functional relationships of GTF2IRD1 in an unbiased manner, yeast two-hybrid libraries were screened, isolating 38 novel interaction partners, which were validated in mammalian cell lines. These relationships illustrate GTF2IRD1 function, as the isolated partners are mostly involved in chromatin modification and transcriptional regulation, whilst others indicate an unexpected role in connection with the primary cilium. Mapping of the sites of protein interaction also indicates key features regarding the evolution of the GTF2IRD1 protein. These data provide a visual and molecular basis for GTF2IRD1 nuclear function that will lead to an understanding of its role in brain, behaviour and human disease.

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Abbreviations

hESC:

Human embryonic stem cells

PLA:

Proximity ligation assay

STED:

Stimulated emission depletion

WBS:

Williams–Beuren syndrome

Y2H:

Yeast two-hybrid

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Acknowledgments

We thank Kylie M. Taylor for her technical assistance. We are grateful for the plasmid constructs provided by the researchers detailed in the Supplementary Table 1. We extend thanks to the Biomedical Imaging Facility, from the Mark Wainwright Analytical Centre at UNSW Australia for their training and support for the microscopy techniques. PC-M and CPC are recipients of a CONICYT-Becas Chile scholarship from the Government of Chile.

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Correspondence to Stephen J. Palmer.

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This work was supported by the National Health and Medical Research Council of Australia (Project Grant 1049639).

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Carmona-Mora, P., Widagdo, J., Tomasetig, F. et al. The nuclear localization pattern and interaction partners of GTF2IRD1 demonstrate a role in chromatin regulation. Hum Genet 134, 1099–1115 (2015). https://doi.org/10.1007/s00439-015-1591-0

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