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Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS

ABSTRACT: Forkhead box protein P1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in 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 in vitro using gene expression microarrays and chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. Transcriptome-wide analysis of Foxp1-transfected striatal cells revealed widespread expression changes of genes related to immune signaling, cancer, transcriptional regulation, and a curated Huntington’s disease (HD) signaling pathway. Integrating the microarray expression dataset with Foxp1 binding sequences determined from ChIP-seq analysis resulted in 75 direct targets of Foxp1, which included Foxp1 itself, which were also related to immune processes and the category “genetic disorder”. These findings demonstrate that Foxp1 is a primary transcriptional repressor of immunological-related gene expression in striatal cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE31560 | GEO | 2011/11/01

SECONDARY ACCESSION(S): PRJNA145685

REPOSITORIES: GEO

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Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS

Project description:Forkhead box protein P1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in 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 in vitro using gene expression microarrays and chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. Transcriptome-wide analysis of Foxp1-transfected striatal cells revealed widespread expression changes of genes related to immune signaling, cancer, transcriptional regulation, and a curated Huntington’s disease (HD) signaling pathway. Integrating the microarray expression dataset with Foxp1 binding sequences determined from ChIP-seq analysis resulted in 75 direct targets of Foxp1, which included Foxp1 itself, which were also related to immune processes and the category “genetic disorder”. These findings demonstrate that Foxp1 is a primary transcriptional repressor of immunological-related gene expression in striatal cells. n=3 wt STHdh striatal cells and n=3 Foxp1-transfected STHdh striatal cells

2011-11-01 | E-GEOD-31560 | biostudies-arrayexpress

Foxp1 drives striatal projection neuron specification and organization via cell-type specific mechanism

Project description:The molecular mechanisms that underlie striatal development and organization remain largely unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and demonstrate that Foxp1 specifies a subpopulation of indirect pathway spiny projection neurons (iSPNs) while maintaining the striosome-matrix architecture through molecular mechanisms mediated by direct pathway spiny projection neurons (dSPNs). Functionally, Foxp1 alters striatal projection patterns both cell-autonomously and non-autonomously. We connect these changes in striatal circuitry to distinct behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. These data reveal novel cell-type specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development

2020-04-13 | GSE125290 | GEO

Gene expression in the striatum of Nestin-Cre (Foxp1-/-) mice in comparison to WT animals at embryonic day (E)18.5

Project description:To define the genes and pathways which are influenced by Foxp1 in the striatum at embryonic stage (E)18.5 we performed a microarray expression study comparing gene expression in striatal tissue from WT and Nestin-Cre (Foxp1-/-) animals.

2019-10-03 | GSE138337 | GEO

The forkhead transcription factor FOXP1 profile in B-cells and B-cell lymphoma cell lines

Project description:Expression of the forkhead transcription factor FOXP1 is essential for early B cell development, whereas downregulation of FOXP1 at the germinal center (GC) stage is required for GC B cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, being associated with poor prognosis. Here, by gene expression microarray [GSE51382] and quantitative RT-PCR analysis upon ectopic overexpression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immunoprecipitation-sequencing (ChIP-seq), we established that FOXP1 directly represses expression of PRDM1, IRF4, and XBP1, transcriptional master regulators of plasma cell (PC) differentiation. In accordance, FOXP1 is prominently expressed in primary human naive and MBCs but expression strongly decreases during plasma PC differentiation. Moreover, as compared to IgM+ MBCs, IgG+ MBCs combine lower expression of FOXP1 with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant overexpression of FOXP1 might contribute to lymphomagenesis by blocking terminal B cell differentiation.

2015-05-19 | GSE69009 | GEO

The forkhead transcription factor FOXP1 profile in B-cells and B-cell lymphoma cell lines

2015-05-19 | E-GEOD-69009 | biostudies-arrayexpress

FOXP1 orchestration of ASD-relevant signaling pathways.

Project description:Mutations in the gene encoding the transcription factor forkhead box P1 or FOXP1 occur in patients with neurodevelopmental disorders, including autism. However, the function of FOXP1 in the brain remains mostly unknown. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and mouse brain and demonstrate a conserved role for FOXP1 transcriptional regulation of autism and Fragile X Mental Retardation Protein (FMRP) mediated pathways. Coexpression networks support a role for Foxp1 in neuronal activity, and we show that Foxp1 is necessary for neuronal excitability. Using a Foxp1 mouse model, we observe defects in ultrasonic vocalizations. This behavioral phenotype is reflected at the genomic level as striatal Foxp1-regulated overlap with genes known to be important in rodent vocalizations. These data support an integral role for FOXP1 in regulating signaling pathways vulnerable in developmental disorders and the specific regulation of pathways important for vocal communication. We carried out RNA-sequencing (RNA-seq) and ChIP-sequencing of human neural progenitors cells. We carried out RNA-sequencing (RNA-seq) of mouse striatal tissue, mouse hippocampal tissue and mouse cortical tissue. For the RNA-seq, four indipendent replicates were used for the neural progenitor cells and mouse tissues. For the Chip-seq, a single neural progenitor cell line was used.

2015-10-26 | E-GEOD-62718 | biostudies-arrayexpress

Upregulated forkhead-box A3 elevates the expression of forkhead-box A1 and forkhead-box A2 to promote metastasis in esophageal cancer.

Project description:Esophageal cancer (EC) is one of the most lethal cancers currently known. Members of the forkhead-box A (FOXA) family, including FOXA1 and FOXA2, have been reported to regulate EC progression. However, the role of FOXA3, which is another FOXA member, has not yet been investigated. In the present study, public dataset analyses and immunohistochemistry of 96 samples from patients with EC were performed to determine the potential roles of FOXA3 in EC. The results revealed that FOXA3 was significantly upregulated in EC tumor tissues and Barrett's esophagus tissues. In addition, FOXA3 upregulation was positively associated with tumor invasion, distant metastasis, tumor-node-metastasis stage and shorter overall survival in patients with EC, and multivariate analysis identified FOXA3 as an independent prognostic marker. In vitro experiments demonstrated that the migratory and invasive abilities of EC109 and EC9706 cell lines were inhibited following FOXA3 knockdown. Notably, FOXA3 expression levels were positively correlated with FOXA1 and FOXA2 expression levels according to The Cancer Genome Atlas dataset analysis. Furthermore, FOXA3 knockdown decreased the expression levels of FOXA1 and FOXA2 in EC109 and EC9706 cell lines. Conversely, FOXA1 or FOXA2 overexpression compensated for the effects of FOXA3 knockdown on the migratory and invasive capacities of EC cells. In conclusion, the present study demonstrated that FOXA3 upregulation in EC cells promoted metastasis through regulation of other FOXA members.

| S-EPMC6444456 | biostudies-literature

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

Project description: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.

| S-EPMC3384380 | biostudies-literature

FOXP1 orchestration of ASD-relevant signaling pathways.

2015-10-26 | GSE62718 | GEO

Integrated genomics and proteomics to define huntingtin CAG length-dependent molecular networks in HD mouse brains

Project description:To gain insight into how mutant Huntingtin (mHTT) CAG repeat length may modify Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat length. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHTT CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels and validated 21 striatal module genes as modifiers of mHtt toxicities in vivo.

2016-02-16 | PXD003442 | Pride

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