B-cell leukemia/lymphoma 11B (Bcl11b) is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in combination with genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. ChIP-seq analysis demonstrated that Bcl11b bound a mixture of coding and non-coding sequences that were within 10 kb of the transcription start site of an annotated gene. Integrating all ChIP-seq hits with the microarray expression data, 248 direct targets of Bcl11b were identified. Functional analysis on the integrated gene target list identified several zinc-finger encoding genes as Bcl11b targets, and further revealed a significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. Analysis of ChIP-seq binding regions revealed significant consensus DNA binding motifs for Bcl11b. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. Specific targeting of the Bcl11b-DNA interaction could represent a novel therapeutic approach to lowering BDNF signaling specifically in striatal cells.
References
[1]
Graybiel AM (1995) The basal ganglia. Trends Neurosci 18: 60–62.
[2]
Graybiel AM (2005) The basal ganglia: learning new tricks and loving it. Curr Opin Neurobiol 15: 638–644.
[3]
Knowlton BJ, Mangels JA, Squire LR (1996) A neostriatal habit learning system in humans. Science 273: 1399–1402.
[4]
Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357–381.
[5]
Arlotta P, Molyneaux BJ, Jabaudon D, Yoshida Y, Macklis JD (2008) Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J Neurosci 28: 622–632.
[6]
Desplats PA, Kass KE, Gilmartin T, Stanwood GD, Woodward EL, et al. (2006) Selective deficits in the expression of striatal-enriched mRNAs in Huntington's disease. J Neurochem 96: 743–757.
[7]
Leid M, Ishmael JE, Avram D, Shepherd D, Fraulob V, et al. (2004) CTIP1 and CTIP2 are differentially expressed during mouse embryogenesis. Gene Expr Patterns 4: 733–739.
[8]
Liu P, Li P, Burke SCritical roles of Bcl11b in T-cell development and maintenance of T-cell identity. Immunol Rev 238: 138–149.
[9]
Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5: 311–322.
[10]
Nilsson P, Iwata N, Muramatsu S, Tjernberg LO, Winblad B, et al. (2010) Gene therapy in Alzheimer's disease - potential for disease modification. J Cell Mol Med 14: 741–757.
[11]
Pardon MC (2010) Role of neurotrophic factors in behavioral processes: implications for the treatment of psychiatric and neurodegenerative disorders. Vitam Horm 82: 185–200.
[12]
Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, et al. (2000) Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Mol Genet 9: 2799–2809.
[13]
Bateman E (1998) Autoregulation of eukaryotic transcription factors. Prog Nucleic Acid Res Mol Biol 60: 133–168.
[14]
Desplats PA, Lambert JR, Thomas EA (2008) Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease. Neurobiol Dis 31: 298–308.
[15]
Bailey TL, Williams N, Misleh C, Li WW (2006) MEME: discovering and analyzing DNA and protein sequence motifs. Nucleic Acids Res 34: W369–373.
[16]
Xie X, Rigor P, Baldi P (2009) MotifMap: a human genome-wide map of candidate regulatory motif sites. Bioinformatics 25: 167–174.
[17]
Wingender E (2008) The TRANSFAC project as an example of framework technology that supports the analysis of genomic regulation. Brief Bioinform 9: 326–332.
[18]
Avram D, Fields A, Pretty On Top K, Nevrivy DJ, Ishmael JE, et al. (2000) Isolation of a novel family of C(2)H(2) zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors. J Biol Chem 275: 10315–10322.
[19]
Lin HB, Jurk M, Gulick T, Cooper GM (1999) Identification of COUP-TF as a transcriptional repressor of the c-mos proto-oncogene. J Biol Chem 274: 36796–36800.
[20]
Avram D, Fields A, Senawong T, Topark-Ngarm A, Leid M (2002) COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein. Biochem J 368: 555–563.
[21]
Badis G, Berger MF, Philippakis AA, Talukder S, Gehrke AR, et al. (2009) Diversity and complexity in DNA recognition by transcription factors. Science 324: 1720–1723.
[22]
Gottesfeld JM, Neely L, Trauger JW, Baird EE, Dervan PB (1997) Regulation of gene expression by small molecules. Nature 387: 202–205.
[23]
Trauger JW, Baird EE, Dervan PB (1996) Recognition of DNA by designed ligands at subnanomolar concentrations. Nature 382: 559–561.
[24]
Foster GA, Schultzberg M, Kokfelt T, Goldstein M, Hemmings HC Jr, et al. (1988) Ontogeny of the dopamine and cyclic adenosine-3′:5′-monophosphate-regulated phosphoprotein (DARPP-32) in the pre- and postnatal mouse central nervous system. Int J Dev Neurosci 6: 367–386.
[25]
Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19: 185–193.
[26]
Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, et al. (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31:
[27]
Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.
[28]
Luo RX, Postigo AA, Dean DC (1998) Rb interacts with histone deacetylase to repress transcription. Cell 92: 463–473.
[29]
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, et al. (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9: R137.
[30]
Rhead B, Karolchik D, Kuhn RM, Hinrichs AS, Zweig AS, et al. (2010) The UCSC Genome Browser database: update 2010. Nucleic Acids Res 38: D613–619.
[31]
Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, et al. (2008) The HDAC Inhibitor, 4b, Ameliorates the Disease Phenotype and Transcriptional Abnormalities in Huntington's Disease Transgenic Mice. Proc Natl Acad Sci U S A 105: 15564–15569.
