Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: implications for transcriptional dysregulation in Huntington disease

• Published in: Human molecular genetics Vol. 21; no. 14; pp. 3097 - 3111
• Main Authors: Tang, Bin, Becanovic, Kristina, Desplats, Paula A., Spencer, Brian, Hill, Austin M., Connolly, Colum, Masliah, Eliezer, Leavitt, Blair R., Thomas, Elizabeth A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.07.2012
• Subjects: Animal models; Animals; Biological and medical sciences; Brain; Brain - metabolism; Cell interactions; Cell physiology; Central nervous system; Central Nervous System - immunology; Chemokines; Cytokines; Data processing; Development; Disease Models, Animal; DNA microarrays; Down-Regulation; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp1 protein; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene regulation; Genetics of eukaryotes. Biological and molecular evolution; Humans; Huntingtin; Huntington Disease - genetics; Huntington Disease - immunology; Huntington Disease - metabolism; Huntington's disease; Mice; Mice, Transgenic; Molecular and cellular biology; Molecular genetics; Neostriatum; Repressor Proteins - genetics; Repressor Proteins - metabolism; Repressors; Signal Transduction; Transcription factors; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Transgenic mice; Nervous system diseases; Huntingtin; Transcription; Huntington disease; Transcription repressor; Protein A; Genetic disease; Cerebral disorder; Signal transduction; Central nervous system disease; Genetics; Degenerative disease; Extrapyramidal syndrome; Transcription factor FOXP1
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/dds132

Forkhead box protein p1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in central nervous system (CNS) development, but its role in the mature brain is unknown. In order to ascertain functional roles for Foxp1 in the CNS, we have identified gene targets for Foxp1 both in vitro and in vivo using genome-wide expression microarrays and chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. We found that mouse Foxp1 overexpression in striatal cells elicited expression changes of genes related to immune signaling, transcriptional regulation and a manually curated Huntington's disease (HD)-signaling pathway. Similar results were found when the gene expression data set was integrated with Foxp1-binding data determined from ChIP-seq analysis. In vivo lentiviral-mediated overexpression of human FOXP1 in the context of mutant huntingtin (Htt) protein resulted in a robust downregulation of glial cell-associated, immune genes, including those encoding a variety of cytokines and chemokines. Furthermore, Foxp1-induced expression changes were significantly negatively correlated with those changes elicited by mutant Htt protein in several different HD mouse models, and most significantly in post-mortem caudate from human HD subjects. We finally show that Foxp1 interacts with mutant Htt protein in mouse brain and is present in nuclear Htt aggregates in the striatum of R6/1 transgenic mice. These findings implicate Foxp1 as a key repressor of immune signaling in the CNS and suggest that the loss of Foxp1-mediated gene regulation in HD contributes to the immune dysfunction in this disease. We further suggest that Foxp1-regulated pathways might be important mediators of neuronal-glial cell communication.