Previously, we demonstrated that when RA signal cannot be integrated at RARα, because RARα is either not expressed, or has acquired genetic mutations that make it non-functional, the chromatin associated with RARβ2 falls into an aberrant exacerbated state of repression, which is unresponsive to RA [9].
The chromatin at these genes acquired an exacerbated repressed state, or state "of no return".
Apparently, the abrogation of RARα function, be it due to RARα silencing/genetic mutations, or derangement of a factor upstream of RARα (e.g. CRABP2), results in the conversion of the chromatin of RARα-regulated genes from an inactive, yet poised, state permissive for transcription into an exacerbated repressed state that is non permissive for transcription.
Apparently, the chromatin at both RARβ2 and CRBP1 was converted from a state poised for transcription to an exacerbated repressed state unresponsive to RA, which could be reverted only by treatment with the HDAC inhibitor Trichostatin A (TSA) (Fig. 2D, top and bottom).
Likewise, our results indicate that estrogen-deficient female mice exposed to arsenic experience an exacerbated diabetic state that resembles type 2 diabetes.
Therefore, BT appears to provoke an exacerbated inflammatory state due to the bacterial challenge to the GALT during their traffic through mesenteric lymphatic tissue rather than the quantitative physical presence of the bacteria in the systemic compartment, therefore suggesting a distinctive GALTrelated host inflammatory response associated with the BT phenomena.
Statistically significant differences were only found in the Pseudomonas genus, which had a higher relative abundance in PA-colonised patients in both the stable and the exacerbated state (Fig. 1, p = 0.019 and p = 0.003 respectively, Mann–Whitney U test).
Patients were eligible if they could be classified as clinically stable (i.e., in a non-exacerbated state and free from systemic antibiotic therapy for at least thirty days), and had no reportable cold or flu-like symptoms in the previous thirty days.
In this analysis the bacterial community obtained during an exacerbation in PA-colonised patients showed a closer similarity to the microbiome of non-PA-colonised severe COPD participants, in both stable and exacerbated states, than to the microbiome recovered from PA-colonised patients during their stability periods.
In different cell systems, and using different mechanistic approaches, we previously demonstrated that an impaired RARα signalling, due to derangement/loss of RARα itself, confers an exacerbated repressed chromatin state, marked by repressive epigenetic changes at several RA-responsive genes downstream of RARα [7] [9].
