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

Michele Gabriele, Anneke T. Vulto-van Silfhout, Pierre Luc Germain, Alessandro Vitriolo, Raman Kumar, Evelyn Douglas, Eric Haan, Kenjiro Kosaki, Toshiki Takenouchi, Anita Rauch, Katharina Steindl, Eirik Frengen, Doriana Misceo, Christeen Ramane J. Pedurupillay, Petter Stromme, Jill A. Rosenfeld, Yunru Shao, William J. Craigen, Christian P. Schaaf, David Rodriguez-Buritica & 31 others Laura Farach, Jennifer Friedman, Perla Thulin, Scott D. McLean, Kimberly M. Nugent, Jenny Morton, Jillian Nicholl, Joris Andrieux, Asbjørg Stray-Pedersen, Pascal Chambon, Sophie Patrier, Sally A. Lynch, Susanne Kjaergaard, Pernille M. Tørring, Charlotte Brasch-Andersen, Anne Ronan, Arie van Haeringen, Peter J. Anderson, Zöe Powis, Han G. Brunner, Rolph Pfundt, Janneke H.M. Schuurs-Hoeijmakers, Bregje W.M. van Bon, Stefan Lelieveld, Christian Gilissen, Willy M. Nillesen, Lisenka E.L.M. Vissers, Jozef Gecz, David A. Koolen, Giuseppe Testa, Bert B.A. de Vries

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

LanguageEnglish
Pages907-925
Number of pages19
JournalAmerican Journal of Human Genetics
Volume100
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • H3K27Ac
  • YY1
  • chromatin
  • enhancer
  • epigenetics
  • haploinsufficiency
  • intellectual disability
  • neurodevelopment
  • syndrome
  • transcription factor

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Gabriele, M., Vulto-van Silfhout, A. T., Germain, P. L., Vitriolo, A., Kumar, R., Douglas, E., ... de Vries, B. B. A. (2017). YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. American Journal of Human Genetics, 100(6), 907-925. https://doi.org/10.1016/j.ajhg.2017.05.006
Gabriele, Michele ; Vulto-van Silfhout, Anneke T. ; Germain, Pierre Luc ; Vitriolo, Alessandro ; Kumar, Raman ; Douglas, Evelyn ; Haan, Eric ; Kosaki, Kenjiro ; Takenouchi, Toshiki ; Rauch, Anita ; Steindl, Katharina ; Frengen, Eirik ; Misceo, Doriana ; Pedurupillay, Christeen Ramane J. ; Stromme, Petter ; Rosenfeld, Jill A. ; Shao, Yunru ; Craigen, William J. ; Schaaf, Christian P. ; Rodriguez-Buritica, David ; Farach, Laura ; Friedman, Jennifer ; Thulin, Perla ; McLean, Scott D. ; Nugent, Kimberly M. ; Morton, Jenny ; Nicholl, Jillian ; Andrieux, Joris ; Stray-Pedersen, Asbjørg ; Chambon, Pascal ; Patrier, Sophie ; Lynch, Sally A. ; Kjaergaard, Susanne ; Tørring, Pernille M. ; Brasch-Andersen, Charlotte ; Ronan, Anne ; van Haeringen, Arie ; Anderson, Peter J. ; Powis, Zöe ; Brunner, Han G. ; Pfundt, Rolph ; Schuurs-Hoeijmakers, Janneke H.M. ; van Bon, Bregje W.M. ; Lelieveld, Stefan ; Gilissen, Christian ; Nillesen, Willy M. ; Vissers, Lisenka E.L.M. ; Gecz, Jozef ; Koolen, David A. ; Testa, Giuseppe ; de Vries, Bert B.A. / YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 6. pp. 907-925.
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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.",
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Gabriele, M, Vulto-van Silfhout, AT, Germain, PL, Vitriolo, A, Kumar, R, Douglas, E, Haan, E, Kosaki, K, Takenouchi, T, Rauch, A, Steindl, K, Frengen, E, Misceo, D, Pedurupillay, CRJ, Stromme, P, Rosenfeld, JA, Shao, Y, Craigen, WJ, Schaaf, CP, Rodriguez-Buritica, D, Farach, L, Friedman, J, Thulin, P, McLean, SD, Nugent, KM, Morton, J, Nicholl, J, Andrieux, J, Stray-Pedersen, A, Chambon, P, Patrier, S, Lynch, SA, Kjaergaard, S, Tørring, PM, Brasch-Andersen, C, Ronan, A, van Haeringen, A, Anderson, PJ, Powis, Z, Brunner, HG, Pfundt, R, Schuurs-Hoeijmakers, JHM, van Bon, BWM, Lelieveld, S, Gilissen, C, Nillesen, WM, Vissers, LELM, Gecz, J, Koolen, DA, Testa, G & de Vries, BBA 2017, 'YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction', American Journal of Human Genetics, vol. 100, no. 6, pp. 907-925. https://doi.org/10.1016/j.ajhg.2017.05.006

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. / Gabriele, Michele; Vulto-van Silfhout, Anneke T.; Germain, Pierre Luc; Vitriolo, Alessandro; Kumar, Raman; Douglas, Evelyn; Haan, Eric; Kosaki, Kenjiro; Takenouchi, Toshiki; Rauch, Anita; Steindl, Katharina; Frengen, Eirik; Misceo, Doriana; Pedurupillay, Christeen Ramane J.; Stromme, Petter; Rosenfeld, Jill A.; Shao, Yunru; Craigen, William J.; Schaaf, Christian P.; Rodriguez-Buritica, David; Farach, Laura; Friedman, Jennifer; Thulin, Perla; McLean, Scott D.; Nugent, Kimberly M.; Morton, Jenny; Nicholl, Jillian; Andrieux, Joris; Stray-Pedersen, Asbjørg; Chambon, Pascal; Patrier, Sophie; Lynch, Sally A.; Kjaergaard, Susanne; Tørring, Pernille M.; Brasch-Andersen, Charlotte; Ronan, Anne; van Haeringen, Arie; Anderson, Peter J.; Powis, Zöe; Brunner, Han G.; Pfundt, Rolph; Schuurs-Hoeijmakers, Janneke H.M.; van Bon, Bregje W.M.; Lelieveld, Stefan; Gilissen, Christian; Nillesen, Willy M.; Vissers, Lisenka E.L.M.; Gecz, Jozef; Koolen, David A.; Testa, Giuseppe; de Vries, Bert B.A.

In: American Journal of Human Genetics, Vol. 100, No. 6, 01.06.2017, p. 907-925.

Research output: Contribution to journalArticle

TY - JOUR

T1 - YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

AU - Gabriele, Michele

AU - Vulto-van Silfhout, Anneke T.

AU - Germain, Pierre Luc

AU - Vitriolo, Alessandro

AU - Kumar, Raman

AU - Douglas, Evelyn

AU - Haan, Eric

AU - Kosaki, Kenjiro

AU - Takenouchi, Toshiki

AU - Rauch, Anita

AU - Steindl, Katharina

AU - Frengen, Eirik

AU - Misceo, Doriana

AU - Pedurupillay, Christeen Ramane J.

AU - Stromme, Petter

AU - Rosenfeld, Jill A.

AU - Shao, Yunru

AU - Craigen, William J.

AU - Schaaf, Christian P.

AU - Rodriguez-Buritica, David

AU - Farach, Laura

AU - Friedman, Jennifer

AU - Thulin, Perla

AU - McLean, Scott D.

AU - Nugent, Kimberly M.

AU - Morton, Jenny

AU - Nicholl, Jillian

AU - Andrieux, Joris

AU - Stray-Pedersen, Asbjørg

AU - Chambon, Pascal

AU - Patrier, Sophie

AU - Lynch, Sally A.

AU - Kjaergaard, Susanne

AU - Tørring, Pernille M.

AU - Brasch-Andersen, Charlotte

AU - Ronan, Anne

AU - van Haeringen, Arie

AU - Anderson, Peter J.

AU - Powis, Zöe

AU - Brunner, Han G.

AU - Pfundt, Rolph

AU - Schuurs-Hoeijmakers, Janneke H.M.

AU - van Bon, Bregje W.M.

AU - Lelieveld, Stefan

AU - Gilissen, Christian

AU - Nillesen, Willy M.

AU - Vissers, Lisenka E.L.M.

AU - Gecz, Jozef

AU - Koolen, David A.

AU - Testa, Giuseppe

AU - de Vries, Bert B.A.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

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KW - YY1

KW - chromatin

KW - enhancer

KW - epigenetics

KW - haploinsufficiency

KW - intellectual disability

KW - neurodevelopment

KW - syndrome

KW - transcription factor

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DO - 10.1016/j.ajhg.2017.05.006

M3 - Article

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T2 - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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