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

Xiangwei Wang,Shuang Huang,John Cowell,Han-Fei Ding,Hongjuan Cui,Lambert C Ngoka,Bilian Jin,Eun J Lee,Jeong-Hyeon Choi,Yunhong Zha,Liqun Yang,Ling Mao,Mingqiang Ren,Jane Ding,Huidong Shi

doi:10.1186/1471-2164-14-830

Abstract

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

Highlights

Cellular differentiation is characterized by the acquisition of specialized structures and functions, cell cycle exit, and global attenuation of the DNA damage response
Global upregulation of neuronal genes Gene Ontology (GO) analysis of the 879 HOXC9upregulated genes by Database for annotation visualization and integrated discovery (DAVID) [29,30] revealed that they were significantly enriched for genes that control nervous system development such as neuron generation and differentiation, axonogenesis, and synapse formation and organization (Figure 1B and Additional file 2: Table S2, enrichment fold ≥ 2.0, false discovery rate (FDR) ≤1%)
Ingenuity Pathways Analysis (IPA) further revealed a network of HOXC9-upregulated genes relevant to the development and function of sympathetic neurons (Additional file 3: Figure S1). These analyses demonstrate that HOXC9 activates a large number of neuronal genes, providing the molecular mechanism for its ability to induce neuronal differentiation of neuroblastoma cells

Summary

Introduction

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. It has long been recognized that differentiated cells of both normal and tumor origin are defective in the DNA damage response and repair at the global level, displaying a marked increase in sensitivity to ionizing radiation and other DNA damaging agents [1,2,3] Consistent with these observations, recent studies have shown that brain and breast cancer stem cells, a small. Downregulation of HOXC9 expression is significantly associated with poor prognosis in neuroblastoma patients [17,18]

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Discussion

Conclusion