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Open Access Research article

HOXC9 directly regulates distinct sets of genes to coordinate diverse cellular processes during neuronal differentiation

Xiangwei Wang1, Jeong-Hyeon Choi23, Jane Ding24, Liqun Yang6, Lambert C Ngoka2, Eun J Lee25, Yunhong Zha7, Ling Mao8, Bilian Jin25, Mingqiang Ren24, John Cowell24, Shuang Huang25, Huidong Shi25, Hongjuan Cui6* and Han-Fei Ding245*

Author Affiliations

1 Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China

2 Cancer Center, Georgia Regents University, Augusta, GA 30912, USA

3 Department of Biostatistics and Epidemiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA

4 Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA

5 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA

6 State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and System Biology, Southwest University, Chongqing, China

7 Department of Neurology, First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China

8 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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BMC Genomics 2013, 14:830  doi:10.1186/1471-2164-14-830

Published: 25 November 2013

Abstract

Background

Cellular differentiation is characterized by the acquisition of specialized structures and functions, cell cycle exit, and global attenuation of the DNA damage response. It is largely unknown how these diverse cellular events are coordinated at the molecular level during differentiation. We addressed this question in a model system of neuroblastoma cell differentiation induced by HOXC9.

Results

We conducted a genome-wide analysis of the HOXC9-induced neuronal differentiation program. Microarray gene expression profiling revealed that HOXC9-induced differentiation was associated with transcriptional regulation of 2,370 genes, characterized by global upregulation of neuronal genes and downregulation of cell cycle and DNA repair genes. Remarkably, genome-wide mapping by ChIP-seq demonstrated that HOXC9 bound to 40% of these genes, including a large number of genes involved in neuronal differentiation, cell cycle progression and the DNA damage response. Moreover, we showed that HOXC9 interacted with the transcriptional repressor E2F6 and recruited it to the promoters of cell cycle genes for repressing their expression.

Conclusions

Our results demonstrate that HOXC9 coordinates diverse cellular processes associated with differentiation by directly activating and repressing the transcription of distinct sets of genes.

Keywords:
Neuronal differentiation; Cell cycle arrest; DNA damage response; E2F6; HOXC9; Neuroblastoma