Gonghong Wei

Short CV

Regulatory Genomics and Functional Cancer Genetics

Project Leader
Gonghong Wei, Ph.D., Docent, Academy Research Fellow

Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu

Background and Significance

The transcription factors (TFs) in a given genome can be classified into distinct families by structurally conserved DNA-binding domains (DBDs), often with similar DNA recognition properties. However, the members of the family always display distinct functions and activities in various biological processes in cancer and normal development. The likelihood and nature are different in the network hubs of gene transcriptional regulation, which is often composed of intertwined regulatory relationships between TF protein complexes and chromatinized gene regulatory elements, such as promoters, insulators and enhancers (Wei et al. J Biochem 381:1-12, 2004 and Cell Res 15:292:292-300, 2005). Therefore, it is of crucial importance to identify the genome-wide chromatin locations of a given TF with biological significance. Meanwhile, we hypothesized that some cancer risk-associated single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWASs) can disrupt TF–DNA binding at key enhancers and initiate aberrant expression of SNP-linked susceptibility genes. And this, in turn, may result in perturbation of TF regulatory networks that cause cancer initiation and progression.

To address these questions, we carried out genome-wide chromatin location analyses of several driver TFs such as TMPRSS2-ERG, HOXB13, FOXA1 and androgen receptor (AR) (Figure 1), which are often overexpressed and constitutively activated in many clinical prostate cancer tissues. In combination with global ChIP-seq studies of enhancer chromatin marks we have identified thousands of prostate cancer cell-type-specific enhancers. We are using integrative and complementary genome-wide approaches including ChIP-seq, RNA-seq, FAIRE-seq and 3C-derived methods in combination with novel and classic molecular and biochemical assays, and also up-to-date computational and statistical methods. Recently, we found that prostate cancer-associated key TFs including HOXB13, FOXA1 and ERG extensively cooperate with AR signaling to regulate target genes that are implicated in prostate cancer cell growth and tumor progression (data not shown). In addition, we found that our integrative genomic data seems to be working well in functional interpretation and mechanistic understanding of GWAS-discovered genetic variants in prostate cancer, including the SNP rs339331, through enhancing HOXB13 chromatin binding to drive up-regulation of the transcription factor gene RFX6, which confers a risk of prostate cancer (Huang et al. Nat Genet 46:126-35, 2014).

Figure 1. Genome-wide mapping of TF binding sites and enhancers in prostate cancer cells. Human chromosomes are shown around the outer ring. Other tracks contain ChIP-seq data of the TFs and enhancer marks as indicated.

Recent Progress

To map prostate cancer gene regulatory networks driven by driver TFs, for the first time, we profiled genome-wide chromatin locations of HOXB13, which is known to be important as regards prostate development and tumor progression. We observed that prostate cancer GWAS SNPs are significantly enriched at HOXB13 binding sites (Huang et al. 2014). Interestingly, the common genetic variant rs339331 at the prostate cancer susceptibility 6q22 locus lies within a functional HOXB13 binding site, and is precisely located at a HOXB13 ChIP-seq peak summit. In a Japanese GWAS, the identification of rs339331 in RFX6 was reported as the SNP most associated with prostate cancer risk (P = 1.6 × 10-12; rs339331 T as strongest risk allele). Interestingly, the significant association between rs339331 and susceptibility to prostate cancer was further observed in African Americans, men of European ancestry and the Chinese population, suggesting that rs339331 is a potential genetic marker to evaluate prostate cancer risk across different ethnic groups.

We provided several lines of evidence to show that HOXB13 and AR favor binding to the risk T allele at rs339331 in vivo. Linkage disequilibrium (LD) analysis based on the 1000 Genome Project indicates that GPRC6A and RFX6 are associated with rs339331 in a strong LD block (Huang et al. 2014). However, the existing genomic data from multiple prostate cancer cells and tissues suggested that only the RFX6 gene is active at 6q22. In addition, we found that RFX6 is markedly upregulated in prostate tumor samples. RFX6 upregulation correlates with prostate cancer progression, suggesting that the expression of RFX6 is a promoter for prostate cancer cell growth and metastatic progression. Interestingly, we recently observed that lower expression of RFX6 correlates with tumor progression and metastasis in other solid tumors of breast, colorectal and gastric cancer. Our study suggests that RFX6 is a plausible causative gene linked to rs339331 conferring a risk of prostate cancer. Consistently, eQTL analysis revealed that the rs339331 T risk allele was significantly correlated with higher RFX6 mRNA levels in a Swedish cohort of prostate cancer samples. We therefore proposed a model in which rs339331 is a DNA-binding motif disruptor for AR/HOXB13 heterodimer, and enhanced chromatin binding of HOXB13 and AR to the T risk allele at rs339331 results in increased RFX6 expression, conferring predisposition to prostate cancer (Figure 2). We are currently working on the genes and pathways that are regulated by the TF RFX6, and we are also investigating the functional roles of RFX6 in other types of cancers (breast, colon and stomach). In addition, we are working towards systems annotation of all prostate cancer risk-associated loci using integrative data sets of regulatory genomics, bioinformatics, statistics and high-throughput eQTL analysis with prostate tumor samples (Whitington et al., in press). Meanwhile, my lab is also actively involved in some fruitful collaboration with other scientists from the University of Oulu, identifying a novel functional genetic variant that predisposes people to primary hip and knee osteoarthritis (Taipale et al., 2015), the University of Helsinki as regards discovering HOXB7 target genes in breast cancer (Heinonen et al., 2015), and Wake Forest University School of Medicine in the USA as regards systematic enrichment analysis of all prostate cancer risk-associated SNPs discovered in GWASs (Chen et al., 2015).  

Figure 2. Graphic representation of our model of the regulatory relationships between HOXB13/AR, rs339331 and RFX6 with potential clinical value for risk prediction and stratification in prostate cancer. HOXB13 and AR bind to the rs339331 region within the RFX6 gene and regulate the expression of RFX6. The prostate cancer risk-associated T allele at rs339331 results in increased HOXB13 and AR chromatin binding and thus upregulates RFX6 expression, which consequently leads to an increased risk of the development of prostate cancer.

Future Goals

The mechanisms by which the aberrant expression of TFs contribute to cancer development is generally not understood, even for the well-studied transcriptional regulators, such as AR, ETS factors and HOX family members. GWASs have identified thousands of SNPs associated with predisposition to various diseases including cancer. However, the molecular mechanisms underlying the causal actions and biological effects of these SNPs remain poorly understood. We will continue to address these questions and aim to see how these SNPs affect TF binding to key enhancers, which in turn alter the SNP-associated gene expression that confers cancer susceptibility. We will carry on systematic analysis of gene regulatory networks downstream of the TFs using classical molecular and biochemical methods, as well as state-of-the-art functional genomics and systems biology approaches – the combined strength of genomics, genetics and bioinformatics.

Selected Publications

  1. Whitington T, Gao P, Song W, Ross-Adams H, Lamb AD, Yang Y, Svezia I, Klevebring D, Mills IG, Karlsson R, Halim S, Dunning MJ, Egevad L, Warren AY, Neal DE, Grönberg H, Lindberg J, Wei GH, Wiklund F. Gene regulatory mechanisms underpinning prostate cancer susceptibility. Nature Genetics. 48:387-397, 2016
    Highlighted in: Prostate Cancer Risk Loci Are Associated with Gene Regulatory Mechanisms. Cancer Discovery 6:OF13, 2016
  2. Du M, Tillmans L, Gao J, Gao P, Yuan T, Dittmar RL, Song W, Yang Y, Sahr N, Wang T, Wei GH, Thibodeau SN, Wang L. Chromatin interactions and candidate genes at ten prostate cancer risk loci. Scientific Reports. 6:23202, 2016
  3. Taipale M, Jakkula E, Kämäräinen OP, Gao P, Skarp S, Barral S, Kiviranta I, Kröger H, Ott J, Wei GH, Ala-Kokko L, Männikkö M. Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis. Osteoarthritis Cartilage. pii: S1063-4584(15)01390-4, 2015
  4. Heinonen H, Lepikhova T, Sahu B, Pehkonen H, Pihlajamaa P, Louhimo R, Gao P, Wei GH, Hautaniemi S, Jänne OA, Monni O. Identification of several potential chromatin binding sites of HOXB7 and its downstream target genes in breast cancer. Int J Cancer. 137:2374-2383, 2015
  5. Chen H, Yu H, Wang J, Zhang Z, Gao Z, Chen Z, Lu Y, Liu W, Jiang D, Zheng SL, Wei GH, Issacs WB, Feng J, Xu J. Systematic enrichment analysis of potentially functional regions for 103 prostate cancer risk-associated loci. Prostate. 75:1264-1276, 2015
  6. Munne PM, Gu Y, Tumiati M, Gao P, Koopal S, Uusivirta S, Sawicki J,Wei GH, Kuznetsov SG. TP53 supports basal-like differentiation of mammary epithelial cells by preventing translocation of deltaNp63 into nucleoli. Sci Rep. 4:4663, 2014
  7. Huang Q, Whitington T, Gao P, Lindberg JF, Yang Y, Sun J, Väisänen MR, Szulkin R, Annala M, Yan J, Egevad LA, Zhang K, Lin R, Jolma A, Nykter M, Manninen A, Wiklund F, Vaarala MH, Visakorpi T, Xu J, Taipale J, Wei GH. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nature Genetics. 46:126-135, 2014

Highlighted in:
** HOXB13, RFX6 and prostate cancer risk. Nature Genetics. 46:94-95, 2014
** Prostate cancer: HOXB13 and a SNP collaborate to increase riskNature Reviews Urology. 11:64, 2014
** A Prostate Cancer–Associated SNP Increases HOXB13 Binding. Cancer Discovery  4:268, 2014
** Recommended by Faculty of 1000: ★★ Very Good, good for teaching, new finding. In F1000Prime, 27 Jan 2014; DOI: 10.3410/f.718228195.793490008
** New evidence highlights the mechanism by which a single nucleotide polymorphism enhances prostate cancer progression. Oncology Central  Jan 17 2014
** New insight into Prostate Cancer susceptibility. CancerIndex Feb 1 2014
** Uusi geneettinen säätelymekanismi eturauhassyöpäriskin taustalla.Duodecim Feb 4 2014

In the news:
** Mechanism affecting risk of prostate cancer found. Science Daily  Jan 10 2014
** Eturauhasyövälle altistava geenimuutos tunnistettu. KALEVA Jan 10 2014
** Eturauhassyöpään johtava geenimuutos löytyi Oulussa. HELSINGIN SANOMAT Jan 10 2014
** Eturauhassyövän riskitekijä löytyiHELSINGIN SANOMAT  Jan 11 2014

  1. Jolma A, Yan J, Whitington T, Toivonen J, Nitta KR, Rastas P, Morgunova E, Enge M, Taipale M, Wei G, Palin K, Vaquerizas JM, Vincentelli R, Luscombe NM, Hughes TR, Lemaire P, Ukkonen E, Kivioja T, and Taipale J. DNA Binding specificities of human transcription factors. Cell. 152:327-339, 2013
  2. Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M, Bonke M, Jolma A, Varjosalo M, Gehrke AR, Yan J, Talukder S, Turunen M, Taipale M, Stunnenberg HG, Ukkonen E, Hughes TR, Bulyk ML, Taipale J. Genome-Wide Analysis of ETS Family DNA-Binding in vitro and in vivo. EMBO J. 29:2147-2160, 2010
  3. Jolma A, Kivioja T, Toivonen J, Cheng L, Wei G, Enge M, Taipale M, Vaquerizas JM, Yan J, Sillanpää MJ, Bonke M, Palin K, Talukder S, Hughes TR, Luscombe NM, Ukkonen E, Taipale J. Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities. Genome Research. 20:861-873, 2010
  4. Tuupanen S, Turunen M, Lehtonen R, Hallikas O, Vanharanta S, Kivioja T, Björklund M, Wei G, Yan J, Niittymäki I, Mecklin JP, Järvinen H, Ristimäki A, Di-Bernardo M, East P, Carvajal-Carmona L, Houlston RS, Tomlinson I, Palin K, Ukkonen E, Karhu A, Taipale J, Aaltonen LAThe common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nature Genetics. 41:885-890, 2009
  5. Wei GH, Zhao GW, Song W, Hao DL, Lv X, Liu DP, Liang CC. Mechanisms of human gamma-globin transcriptional induction by apicidin involves p38 signaling to chromatin. Biochemical and Biophysical Research Communications.363:889-894, 2007
  6. Wei GH, Liu DP, Liang CC. Chromatin domain boundaries: insulators and beyond. Cell Research. 15:292-300, 2005
  7. Wei GH, Liu DP, Liang CC. Charting gene regulatory networks: strategies, challenges and perspectives. Biochemical Journal. 381:1-12, 2004

Research Group Members

Project Leader:
Gonghong Wei, Ph.D. (Academy of Finland)

Senior and Post-doctoral Investigators:
Hang-Mao Lee, Ph.D. (University of Oulu)

Ph.D. Students:
Ping Gao, M.Sc. (Academy of Finland and China Scholarship Council)
Qin Zhang, M.Sc. (Academy of Finland and Foundation)
Nikolaos Giannareas (University of Oulu)
Jihan Xia (University of Oulu)

Project Researcher:
Yuehong Yang, M.Sc. (Academy of Finland)

Project Workers:
Sufyan Suleman, B.Sc. (Foundation)

Main source of salary in brackets.

Foreign Scientists, 9

National and International Activities

Visiting Researchers in 2015 (over two weeks)

Gonghong Wei, Ph.D. (24 March – 15 April 2015) had a short-term international research visit to professor Depei Liu’s lab at Institute of Basic Medical Sciences, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China

Chandan Thapa, B.Sc. (20 April - 20 May 2015), a master student from International Master Program, University of Oulu, Oulu, Finland

Last updated: 28.10.2016