Soo Seok Hwanga, Young Uk Kima, Sumin Leea, Sung Woong Janga, Min Kyung Kima, Byung Hee Koha, Wonyong Leea, Joomyeong Kimb, Abdallah Souabnic, Meinrad Busslingerc, and Gap Ryol Leea,1
aDepartment of Life Science, Sogang University, Seoul, Korea 121-742;
bDepartment of Biological Sciences, Louisiana State University, Baton Rouge, LA; and
cResearch Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria
Edited* by Richard A. Flavell, Howard Hughes Medical Institute and Yale School of Medicine, New Haven, CT, and approved November 9, 2012 (received for review August 23, 2012)
The Th2 locus control region (LCR) has been shown to be important in efficient and coordinated cytokine gene regulation during Th2 cell differentiation. However, the molecular mechanism for this is poorly understood. To study the molecular mechanism of the Th2 LCR, we searched for proteins binding to it. We discovered that transcription factor YY1 bound to the LCR and the entire Th2 cytokine locus in a Th2-specific manner. Retroviral overexpression of YY1 induced Th2 cytokine expression. CD4-specific knockdown of YY1 in mice caused marked reduction in Th2 cytokine expression, repressed chromatin remodeling, decreased intrachromosomal interactions, and resistance in an animal model of asthma. YY1 physically associated with GATA-binding protein-3 (GATA3) and is required for GATA3 binding to the locus. YY1 bound to the regulatory elements in the locus before GATA3 binding. Thus, YY1 cooperates with GATA3 and is required for regulation of the Th2 cytokine locus and Th2 cell differentiation.
1To whom correspondence should be addressed.
Author contributions: G.R.L. designed research; S.S.H., Y.U.K., S.L., S.W.J., M.K.K., B.H.K., and W.L. performed research; J.K., A.S., and M.B. contributed new reagents/analytic tools; S.S.H. and G.R.L. analyzed data; and G.R.L. wrote the paper.