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Interferon Regulatory Factor 6 Determines Epithelial Cell Development and Immunity 2

ABSTRACT: Intestinal epithelial cells (IECs) form a primary barrier against microbial invasion. Prior studies of enteric pathogens have indicated that IEC defense mechanisms are distinct from those of other cell types. For example, antiviral defense of IECs depends on type III interferon whereas most cell types depend on type I IFN. Interferon regulatory factors (IRFs) are a family of transcription factors with well-described roles in stimulation of IFN cytokines, but IRF6 is unique in its preferential expression by epithelial lineages. IRF6 has primarily been studied in epidermal development, but has relatively unknown roles in the intestinal epithelium. Here, we found that Irf6 KO regulated IFN-stimulated antiviral immunity of IECs but had no effect on macrophages. RNseq analysis of Irf6 KO cells showed significant differences in the IFN-stimulated gene expression program that correlated with the magnitude of antiviral gene stimulation. We also found significant baseline phenotypic and transcriptional changes in Irf6 KO IECs, with reduced rate of growth and preturbation of growth and differentiation pathway genes. Knockout of Irf6 in primary IEC organoids also resulted in slower growth and smaller size. Transcriptional analysis of Irf6 KO organoids indicated reduced expression of genes in the epithelial differentiation pathwya, including Wnt and Notch pathway genes, as well as increased expression of a subset of IFN-stimulated genes. These data indicate a previously unappreciated role of Irf6 in shaping the IEC transcriptome, including baseline epithelial development genes and IFN-stimulated genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE245971 | GEO | 2023/11/01

REPOSITORIES: GEO

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Interferon Regulatory Factor 6 Determines Epithelial Cell Development and Immunity 1

Project description:Intestinal epithelial cells (IECs) form a primary barrier against microbial invasion. Prior studies of enteric pathogens have indicated that IEC defense mechanisms are distinct from those of other cell types. For example, antiviral defense of IECs depends on type III interferon whereas most cell types depend on type I IFN. Interferon regulatory factors (IRFs) are a family of transcription factors with well-described roles in stimulation of IFN cytokines, but IRF6 is unique in its preferential expression by epithelial lineages. IRF6 has primarily been studied in epidermal development, but has relatively unknown roles in the intestinal epithelium. Here, we found that Irf6 KO regulated IFN-stimulated antiviral immunity of IECs but had no effect on macrophages. RNseq analysis of Irf6 KO cells showed significant differences in the IFN-stimulated gene expression program that correlated with the magnitude of antiviral gene stimulation. We also found significant baseline phenotypic and transcriptional changes in Irf6 KO IECs, with reduced rate of growth and preturbation of growth and differentiation pathway genes. Knockout of Irf6 in primary IEC organoids also resulted in slower growth and smaller size. Transcriptional analysis of Irf6 KO organoids indicated reduced expression of genes in the epithelial differentiation pathwya, including Wnt and Notch pathway genes, as well as increased expression of a subset of IFN-stimulated genes. These data indicate a previously unappreciated role of Irf6 in shaping the IEC transcriptome, including baseline epithelial development genes and IFN-stimulated genes.

2023-11-01 | GSE245970 | GEO

HNF4A regulation of transcription profiles in the mouse cecal epithelial cells

Project description:Purpose: HNF4A is a highly conserved nuclear receptor that has been associated with inflammatory bowel diseases. The goal of this study is to determine transcriptional regulation by HNF4A in the cecal IECs.. Methods: Intestinal epithelial cells (IECs) were sorted from the ceca of young adult WT and HNF4A IEC-specific KO mice and sequenced for transcriptome. Differentially expressed genes comparing the WT and HNF4A IEC-KO were determined. Results: Epithelial HNF4A regulates expression of hundreds of genes. HNF4A is particularly required for the expression of a set of immune signaling molecules that are critical for the IEC-intrapithelial lymphocyte crosstalk. Those molecules include members of the butyrophilin-like molecules (Btnl1 and Btnl6) and MHC-I like molecule H2-T3 etc. Expression of the immune signaling molecules was validated by qPCR. Further comparison with HNF4A ChIP-seq datasets confirmed that those genes are also direct HNF4A targets.

2022-06-30 | GSE199415 | GEO

Regulation of gene expression in IECs by HDAC3

Project description:The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that intestinal epithelial cells (IECs) isolated from IBD patients exhibit decreased expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3). Further, genome-wide analyses of murine IECs that lack HDAC3 (HDAC3?IEC) revealed that HDAC3 deficiency resulted in dysregulated gene expression coupled with alterations in histone acetylation. Critically, conventionally-housed HDAC3?IEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3?IEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Strikingly, rederivation of HDAC3?IEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. Collectively, these data indicate that the HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis. In this study, we performed gene expression profiling to examine how the transcriptional profiles in primary live, EpCAM+ IECs from the large intestine differed between control HDAC3FF mice (3 biological replicates) and IEC-intrinsic knockout HDAC3?IEC mice (3 biological replicates).

2013-11-12 | E-GEOD-50188 | biostudies-arrayexpress

The transferrin receptor is required for intestinal epithelial homeostasis

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2015-05-19 | E-GEOD-68984 | biostudies-arrayexpress

HNF4A regulation of transcription profiles in the mouse ileal and colonic epithelial cells

Project description:Purpose: HNF4A is a highly conserved nuclear receptor that has been associated with inflammatory bowel diseases. The goal of this study is to determine and compare transcriptional regulation by HNF4A in the small intestine and large intestine in mice. Methods: Intestinal epithelial cells (IECs) were flow sorted from the ileum and colon of WT and HNF4A IEC-specific KO mice at 21~22 days old and sequenced for transcriptome. Differentially expressed genes in the illeum and colon respectively comparing the WT and HNF4A IEC-KO were determined. Results: HNF4A regulates expression of hundreds of genes in both ileal and colonic IECs. However, many of the DE genes and the magnitude of changes are location specific. In general, a more significant dependancy on HNF4A is found in the colon. HNF4A is particularly required for the expression of a set of immune signaling molecules that are critical for the IEC-intrapithelial lymphocyte crosstalk. Those molecules include members of the butyrophilin-like molecules (Btnl1, Btnl2, Btnl4, and Btnl6) and MHC-I like molecule H2-T3 etc. Expression of the immune signaling molecules was validated by qPCR. Further comparison with HNF4A ChIP-seq datasets and validation with ChIP-qPCR confirmed that those genes are also direct HNF4A targets.

2022-06-30 | GSE199416 | GEO

Regulation of gene expression in IECs by HDAC3 under germ-free conditions

Project description:The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that intestinal epithelial cells (IECs) isolated from IBD patients exhibit decreased expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3). Further, genome-wide analyses of murine IECs that lack HDAC3 (HDAC3ΔIEC) revealed that HDAC3 deficiency resulted in dysregulated gene expression coupled with alterations in histone acetylation. Critically, conventionally-housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Strikingly, rederivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. Collectively, these data indicate that the HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis. In this study, we performed gene expression profiling to examine how the transcriptional profiles in primary live, EpCAM+ IECs from the large intestine differed between germ-free control HDAC3FF mice (3 biological replicates) and germ-free IEC-intrinsic knockout HDAC3ΔIEC mice (3 biological replicates).

2013-11-12 | E-GEOD-50189 | biostudies-arrayexpress

RNA-seq analysis of colonic intestinal epithelial cells (IECs) isolated from naive wild-type C57BL/6 mice, DSS-treated wild-type C57BL/6 mice, Il10-/- C57BL/6 mice and Il10-/- C57BL/6 mice with IEC-specific Rabgef1 deletion

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2019-09-30 | E-MTAB-7315 | biostudies-arrayexpress

Unique expression profile for type-I, -II, and -III IFNs regarding epithelial reorganization in primary epithelial cells

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