Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction / M. Gabriele, A.T. Vulto van Silfhout, P. Germain, A. Vitriolo, R. Kumar, E. Douglas, E. Haan, K. Kosaki, T. Takenouchi, A. Rauch, K. Steindl, E. Frengen, D. Misceo, C.R.J. Pedurupillay, P. Stromme, J.A. Rosenfeld, Y. Shao, W.J. Craigen, C.P. Schaaf, D. Rodriguez Buritica, L. Farach, J. Friedman, P. Thulin, S.D. Mclean, K.M. Nugent, J. Morton, J. Nicholl, J. Andrieux, A. Stray Pedersen, P. Chambon, S. Patrier, S.A. Lynch, S. Kjaergaard, P.M. Tørring, C. Brasch Andersen, A. Ronan, A. van Haeringen, P.J. Anderson, Z. Powis, H.G. Brunner, R. Pfundt, J.H.M. Schuurs Hoeijmakers, B.W.M. van Bon, S. Lelieveld, C. Gilissen, W.M. Nillesen, L.E.L.M. Vissers, J. Gecz, D.A. Koolen, G. Testa, B.B.A. de Vries. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 100:6(2017 Jun 01), pp. 907-925. [10.1016/j.ajhg.2017.05.006]

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

M. Gabriele
Primo
;
P. Germain
Secondo
;
A. Vitriolo;G. Testa
;
2017

Abstract

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
17Q21.31 microdeletion syndrome; potential functions; mental-retardation; demethylase JMJD3; gene-expression; adenovirus E1A; liquid water; KANSL1 cause; stem-cells; mutations
Settore BIO/11 - Biologia Molecolare
Settore BIO/10 - Biochimica
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/13 - Biologia Applicata
Settore MED/04 - Patologia Generale
Settore MED/25 - Psichiatria
Settore MED/38 - Pediatria Generale e Specialistica
Settore MED/39 - Neuropsichiatria Infantile
Settore MED/26 - Neurologia
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/503596
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