Functional characteristics of novel pancreatic Pax6 regulatory elements.
Functional characteristics of novel pancreatic Pax6 regulatory elements.
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DOI：
10.1093/hmg/ddy255
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发表时间：
2018-10-01
影响因子：
3.5
通讯作者：
Gilbert N
中科院分区：
文献类型：
--
作者：
Buckle A;Nozawa RS;Kleinjan DA;Gilbert N
复杂的疾病，如糖尿病，受到全面的转录网络的影响。全基因组关联研究表明，位于胰腺转录因子调控元件中的变体与糖尿病有关，包括与配对盒转录因子Pax6功能相关的变体。成年小鼠Pax6缺失导致经典糖尿病的快速发作，但胰腺Pax6调节剂的全谱尚不清楚。使用的调控元件发现的方法，我们确定了两个新的Pax6胰腺顺式调控元件在一个不良的特点监管沙漠。这两个新的元件，Pax6胰腺顺式调节元件3（PE3）和PE4，位于50和100 kb的上游，并与Pax6启动子和附近的非编码RNA的不同部分相互作用。它们驱动发育中的胰腺和大脑的表达，并编码多个胰腺相关的转录因子结合位点。PE3结合CCCTC结合因子（CTCF），并在胚胎干细胞中被干细胞身份标记物标记，而位于PE4元件中的常见变体影响Pax4（一种已知的胰腺调节因子）的结合，从而改变Pax6基因表达。为了确定这些元件调节基因表达的能力，合成的转录激活因子和抑制因子靶向PE 3和PE 4，调节Pax6基因表达，以及影响邻近基因和长的非编码RNA，暗示Pax6基因座在胰腺功能和糖尿病中。
Complex diseases, such as diabetes, are influenced by comprehensive transcriptional networks. Genome-wide association studies have revealed that variants located in regulatory elements for pancreatic transcription factors are linked to diabetes, including those functionally linked to the paired box transcription factor Pax6. Pax6 deletions in adult mice cause rapid onset of classic diabetes, but the full spectrum of pancreatic Pax6 regulators is unknown. Using a regulatory element discovery approach, we identified two novel Pax6 pancreatic cis-regulatory elements in a poorly characterized regulatory desert. Both new elements, Pax6 pancreas cis-regulatory element 3 (PE3) and PE4, are located 50 and 100 kb upstream and interact with different parts of the Pax6 promoter and nearby non-coding RNAs. They drive expression in the developing pancreas and brain and code for multiple pancreas-related transcription factor-binding sites. PE3 binds CCCTC-binding factor (CTCF) and is marked by stem cell identity markers in embryonic stem cells, whilst a common variant located in the PE4 element affects binding of Pax4, a known pancreatic regulator, altering Pax6 gene expression. To determine the ability of these elements to regulate gene expression, synthetic transcriptional activators and repressors were targeted to PE3 and PE4, modulating Pax6 gene expression, as well as influencing neighbouring genes and long non-coding RNAs, implicating the Pax6 locus in pancreas function and diabetes.
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影响因子：
29
作者：
Akerman I;Tu Z;Beucher A;Rolando DMY;Sauty-Colace C;Benazra M;Nakic N;Yang J;Wang H;Pasquali L;Moran I;Garcia-Hurtado J;Castro N;Gonzalez-Franco R;Stewart AF;Bonner C;Piemonti L;Berney T;Groop L;Kerr-Conte J;Pattou F;Argmann C;Schadt E;Ravassard P;Ferrer J
通讯作者：
Ferrer J
影响因子：
64.8
作者：
通讯作者：
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全基因组关联研究的荟萃分析确定了东亚人 2 型糖尿病的 8 个新位点
影响因子：
30.8
作者：
Cho, Yoon Shin;Chen, Chien-Hsiun;Hu, Cheng;Long, Jirong;Ong, Rick Twee Hee;Sim, Xueling;Takeuchi, Fumihiko;Wu, Ying;Go, Min Jin;Yamauchi, Toshimasa;Chang, Yi-Cheng;Kwak, Soo Heon;Ma, Ronald C. W.;Yamamoto, Ken;Adair, Linda S.;Aung, Tin;Cai, Qiuyin;Chang, Li-Ching;Chen, Yuan-Tsong;Gao, Yutang;Hu, Frank B.;Kim, Hyung-Lae;Kim, Sangsoo;Kim, Young Jin;Lee, Jeannette Jen-Mai;Lee, Nanette R.;Li, Yun;Liu, Jian Jun;Lu, Wei;Nakamura, Jiro;Nakashima, Eitaro;Ng, Daniel Peng-Keat;Tay, Wan Ting;Tsai, Fuu-Jen;Wong, Tien Yin;Yokota, Mitsuhiro;Zheng, Wei;Zhang, Rong;Wang, Congrong;So, Wing Yee;Ohnaka, Keizo;Ikegami, Hiroshi;Hara, Kazuo;Cho, Young Min;Cho, Nam H.;Chang, Tien-Jyun;Bao, Yuqian;Hedman, Asa K.;Morris, Andrew P.;McCarthy, Mark I.;Takayanagi, Ryoichi;Park, Kyong Soo;Jia, Weiping;Chuang, Lee-Ming;Chan, Juliana C. N.;Maeda, Shiro;Kadowaki, Takashi;Lee, Jong-Young;Wu, Jer-Yuarn;Teo, Yik Ying;Tai, E. Shyong;Shu, Xiao Ou;Mohlke, Karen L.;Kato, Norihiro;Han, Bok-Ghee;Seielstad, Mark
通讯作者：
Seielstad, Mark
影响因子：
2.6
作者：
Griffin, C;Kleinjan, DA;van Heyningen, V
通讯作者：
van Heyningen, V
影响因子：
3.5
作者：
Alfano, G;Vitiello, C;Banfi, S
通讯作者：
Banfi, S