Tammimies Kristiina, Tapia-Páez Isabel, Rüegg Joëlle, Rosin Gustaf, Kere Juha, Gustafsson Jan-Åke, Nalvarte Ivan
Department of Biosciences and Nutrition, Karolinska Institutet, SE-14183 Huddinge, Sweden.
Mol Endocrinol. 2012 Apr;26(4):619-29. doi: 10.1210/me.2011-1376. Epub 2012 Mar 1.
Estrogen is involved in numerous physiological processes such as growth, differentiation, and function of the male and female reproductive tissues. In the developing brain, estrogen signaling has been linked to cognitive functions, such as learning and memory; however, the molecular mechanisms underlying this phenomenon are poorly understood. We have previously shown a link between developmental dyslexia and estrogen signaling, when we studied the functional interactions between the dyslexia candidate protein DYX1C1 and the estrogen receptors α (ERα) and β (ERβ). Here, we investigate the 17β-estradiol (E2)-dependent regulation of dyslexia susceptibility 1 candidate 1 (DYX1C1) expression. We demonstrate that ERβ, not ERα, binds to a transcriptionally active cis-regulatory region upstream of DYX1C1 transcriptional start site and that DYX1C1 expression is enhanced by E2 in a neuroblastoma cell line. This regulation is dependent on transcription factor II-I and liganded ERβ recruitment to this region. In addition, we describe that a single nucleotide polymorphism previously shown to be associated with dyslexia and located in the cis-regulatory region of DYX1C1 may alter the epigenetic and endocrine regulation of this gene. Our data provide important molecular insights into the relationship between developmental dyslexia susceptibility and estrogen signaling.
雌激素参与众多生理过程，如男性和女性生殖组织的生长、分化及功能。在发育中的大脑中，雌激素信号传导与认知功能（如学习和记忆）有关；然而，这种现象背后的分子机制仍知之甚少。我们之前在研究诵读困难候选蛋白DYX1C1与雌激素受体α（ERα）和β（ERβ）之间的功能相互作用时，发现了发育性诵读困难与雌激素信号传导之间的联系。在此，我们研究17β-雌二醇（E2）对诵读困难易感性1候选基因1（DYX1C1）表达的依赖性调控。我们证明，与DYX1C1转录起始位点上游具有转录活性的顺式调控区域结合的是ERβ而非ERα，并且在神经母细胞瘤细胞系中，E2可增强DYX1C1的表达。这种调控依赖于转录因子II-I以及配体化的ERβ募集至该区域。此外，我们描述了先前显示与诵读困难相关且位于DYX1C1顺式调控区域的一个单核苷酸多态性可能会改变该基因的表观遗传和内分泌调控。我们的数据为发育性诵读困难易感性与雌激素信号传导之间的关系提供了重要的分子见解。
