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.
Original language | English |
---|---|
Pages (from-to) | 907-925 |
Number of pages | 19 |
Journal | American Journal of Human Genetics |
Volume | 100 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 1 2017 |
Fingerprint
Keywords
- chromatin
- enhancer
- epigenetics
- H3K27Ac
- haploinsufficiency
- intellectual disability
- neurodevelopment
- syndrome
- transcription factor
- YY1
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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 journal › Article
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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.
AB - 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.
KW - chromatin
KW - enhancer
KW - epigenetics
KW - H3K27Ac
KW - haploinsufficiency
KW - intellectual disability
KW - neurodevelopment
KW - syndrome
KW - transcription factor
KW - YY1
UR - http://www.scopus.com/inward/record.url?scp=85020105976&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020105976&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2017.05.006
DO - 10.1016/j.ajhg.2017.05.006
M3 - Article
C2 - 28575647
AN - SCOPUS:85020105976
VL - 100
SP - 907
EP - 925
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -