Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease

Fossum, Sara L.; Mutolo, Michael J.; Tugores, Antonio; Ghosh, Sujana; Randell, Scott H.; Jones, Lyle V.; Leir, Shih Hsing; Harris, Ann

doi:10.1074/jbc.m117.775304

Cited by 44 publications

(53 citation statements)

References 62 publications

(73 reference statements)

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“…). We used this approach to map tissue‐specific transcriptional networks in HEE cells, which were then validated by relevant functional assays (Fossum et al ., , ; Gosalia et al ., ; Browne et al ., ; Yang et al ., , 2018).…”

Section: Combining Deep Sequencing Protocols To Investigate Transcripmentioning

confidence: 99%

Transcriptional networks in the human epididymis

et al. 2019

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Background: The epithelial lining of the human epididymis is critical for sperm maturation. This process requires distinct specialized functions in the head, body, and tail of the duct. These region-specific properties are maintained by distinct gene expression profiles which are governed by transcription factor networks, non-coding RNAs, and other factors. Materials and methods: We used genome-wide protocols including DNase-seq, RNA-seq and ChIP-seq to characterize open (active) chromatin, the transcriptome and occupancy of specific transcription factors (TFs) respectively, in caput, corpus, and cauda segments of adult human epididymis tissue and primary human epididymis epithelial (HEE) cell cultures derived from them. RNAseq following TF depletion or activation, combined with gene ontology analysis also determined TF targets. Results: Among regional differentially expressed transcripts were epithelial-selective transcription factors (TFs), microRNAs, and antiviral response genes. Caput-enriched TFs included hepatocyte nuclear factor 1 (HNF1) and the androgen receptor (AR), both of which were also predicted to occupy cis-regulatory elements identified as open chromatin in HEE cells. HNF1 targets were identified genome-wide using ChIP-seq, in HEE cells. Next, siRNA-mediated depletion of HNF1 revealed a pivotal role for this TF in coordinating epithelial water and solute transport in caput epithelium. The importance of AR in HEE cells was shown by AR ChIP-seq, and by RNA-seq after synthetic androgen (R1881) treatment. AR has a distinct transcriptional program in the HEE cells and likely recruits different co-factors (RUNX1 and CEBPb) in comparison to those used in prostate epithelium. Discussion and Conclusion: Our data identify many transcription factors that regulate the development and differentiation of HEE cells. Moreover, a comparison between immature and adult HEE cells showed key TFs in the transition to fully differentiated function of this epithelium. These data may help identify new targets to treat male infertility and have the potential to open new avenues for male contraception. COMBINING DEEP SEQUENCING PROTOCOLS TO INVESTIGATE TRANSCRIPTIONAL NETWORKSNext-generation sequencing (NGS) protocols have the capacity to provide precise, in-depth insights into gene regulatory networks in the human epididymis. To investigate human epididymis epithelial function, we used tissue segments and also established differentiated epididymis epithelial cell cultures from the same tissue donors (Leir et al., 2015). Tissue was obtained with IRB approval from patients undergoing inguinal radical

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Section: Combining Deep Sequencing Protocols To Investigate Transcripmentioning

confidence: 99%

Transcriptional networks in the human epididymis

et al. 2019

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“…The motif for Ehf, a gene with expression restricted mostly to cDCs and epithelial cells ( Figure S6A), was enriched in cDC-specific OCRs. This gene has roles in the regulation of inflammation and antigen transport in epithelial cells (Asai and Morrison, 2013;Fossum et al, 2017) and may have a similar function in cDCs.…”

Section: Bcl11b Expressionmentioning

confidence: 99%

The cis-Regulatory Atlas of the Mouse Immune System

Yoshida

Lareau

Ramirez

et al. 2019

Cell

343

421

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Graphical Abstract Highlights d Atlas of 512,595 cis-regulatory elements active in 86 immunologic cell types d Two classes of loci, controlled by either promoter-or enhancer-driven logic d Inference of enhancer elements that activate each gene across differentiation d Context-specificity of enhancer activation by transcription factors Pile-up traces of ATAC-seq signals in Itgax locus. Blue bars in the first row indicate the positions of identified peaks (Pval % 0.05) and the graph in the 2 nd row conservation score among vertebrates. RNA expression for Itgax (Cd11c) gene are indicated by barplots with * where RNA-seq data was not acquired.

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“…Interestingly, the upstream regulators predicted are not part of canonical IL-13R-proximal signaling but are cellular differentiation genes and may be relevant for goblet cell metaplasia in response to any trigger. EGFR (101), EHF (102,103), and TGF-β (104,105) are also involved in IL-17 signaling, and NCOA3 could affect the inflammatory response by interacting with AP-1 and altering cytokine translation (106)(107)(108).…”

Section: Il-13 Induces Donor-dependent Goblet Cell Metaplasia In Primmentioning

confidence: 99%