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Regulatory module network of basic/helix-loop-helix transcription factors in mouse brain

Jing Li1, Zijing J Liu2, Yuchun C Pan3, Qi Liu1, Xing Fu4, Nigel GF Cooper2, Yixue Li5, Mengsheng Qiu2* and Tieliu Shi456*

Author Affiliations

1 School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China

2 Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA

3 School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China

4 Shanghai Information Center for Life Sciences, Chinese Academy of Sciences, Shanghai 200031, China

5 Bioinformatics Center, Key Lab of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

6 Daqing Institute of Biotechnology, Northeast Forestry University, Daqing, Heilongjiang 163316, China

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Genome Biology 2007, 8:R244  doi:10.1186/gb-2007-8-11-r244

Published: 19 November 2007



The basic/helix-loop-helix (bHLH) proteins are important components of the transcriptional regulatory network, controlling a variety of biological processes, especially the development of the central nervous system. Until now, reports describing the regulatory network of the bHLH transcription factor (TF) family have been scarce. In order to understand the regulatory mechanisms of bHLH TFs in mouse brain, we inferred their regulatory network from genome-wide gene expression profiles with the module networks method.


A regulatory network comprising 15 important bHLH TFs and 153 target genes was constructed. The network was divided into 28 modules based on expression profiles. A regulatory-motif search shows the complexity and diversity of the network. In addition, 26 cooperative bHLH TF pairs were also detected in the network. This cooperation suggests possible physical interactions or genetic regulation between TFs. Interestingly, some TFs in the network regulate more than one module. A novel cross-repression between Neurod6 and Hey2 was identified, which may control various functions in different brain regions. The presence of TF binding sites (TFBSs) in the promoter regions of their target genes validates more than 70% of TF-target gene pairs of the network. Literature mining provides additional support for five modules. More importantly, the regulatory relationships among selected key components are all validated in mutant mice.


Our network is reliable and very informative for understanding the role of bHLH TFs in mouse brain development and function. It provides a framework for future experimental analyses.