Hepatocyte nuclear factor (HNF)-3a, -3p8, and -3y are liver transcription factors that mediate the coor-
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain. In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance. Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation. To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined. Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls. These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.
The hepatocyte nuclear factor-3 (HNF-3)/fork head homolog (HFH) proteins are an extensive family of transcription factors, which share homology in the winged helix DNA binding domain. Members of the HFH/winged helix family have been implicated in cell fate determination during pattern formation, in organogenesis, and in cell-type-specific gene expression. In this study we isolated a full-length HFH-3 cDNA clone from a human kidney library which encoded a 351-amino acid protein containing a centrally located winged helix DNA binding domain. We demonstrate that HFH-3 is a potent transcriptional activator requiring 138 C-terminal residues for activity. We used in situ hybridization to demonstrate that HFH-3 expression is restricted to the epithelium of the renal distal convoluted tubules. We determined the HFH-3 DNA binding consensus sequence by in vitro DNA binding site selection using recombinant HFH-3 protein and used this consensus sequence to identify putative HFH-3 target genes expressed there. These putative HFH-3 target genes include the Na/KATPase, Na/H and anion exchangers, E-cadherin, and mineralocorticoid receptor genes as well as genes for the transcription factors HNF-1, vHNF-1, and HNF-4.Deciphering the mechanisms that lead to cell-specific gene transcription is critical for understanding cellular differentiation during mammalian embryogenesis. Differential expression of protein encoding genes occurs at the point of transcriptional initiation (1) and involves the assembly of several well characterized basal factors with TATA-binding protein, TATAbinding protein-associated factors, and RNA polymerase II at the initiation site of the promoter region (2). Promoter and enhancer regions are also composed of multiple DNA sites that interact with sequence-specific transcription factors, which are believed to enhance the recruitment of basal factors to the initiation complex. Cell-restricted gene expression thus relies upon the combinatorial recognition of multiple cis-acting DNA sequences bound by families of cell-specific nuclear factors, which potentiate or repress transcriptional initiation (3). Because transcription factors play a central role in regulating cellular differentiation, the analysis of their molecular structure and expression patterns has facilitated elucidation of regulatory pathways involved in establishing tissue-specific gene transcription. In combination with other cell-specific transcription factors, the hepatocyte nuclear factor-3␣ (HNF-3␣) 1 and -3 proteins regulate cell-specific transcription in hepatocytes (4) and in respiratory (5-8) and intestinal epithelium (9). The HNF-3/fork head homolog (HFH) proteins are an extensive family of transcription factors that share homology in the winged helix DNA binding domain (10
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