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
Laboratory of Stem Cell Epigenetics, Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Am J Hum Genet. 2017 Jun 1;100(6):907-925. doi: 10.1016/j.ajhg.2017.05.006.
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.
阴阳1（YY1）是一种著名的锌指转录因子，在正常发育和恶性肿瘤中发挥着关键作用。YY1既可以作为基因表达的抑制因子，也可以作为激活因子。我们已经鉴定出23名患有YY1新发突变或缺失且具有认知障碍、行为改变、宫内生长受限、喂养问题和各种先天性畸形等综合征表型特征的个体。我们综合的临床和分子数据将“YY1综合征”定义为一种单倍剂量不足综合征。通过用识别该蛋白两端的抗体对受影响个体细胞中与YY1结合的染色质进行免疫沉淀，我们发现YY1缺失和错义突变导致YY1结合的全面丧失，而在高占据位点有优先保留。最后，我们发现特别是在与YY1结合的增强子上广泛存在H3K27乙酰化缺失，这突出了YY1在增强子调控中的关键作用。总的来说，这些结果确定了一种由YY1单倍剂量不足通过关键转录调节因子失调引起的临床综合征。
